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WO2023154953A1 - Polypeptides gdf15 pour le traitement et la prévention de maladies auto-immunes - Google Patents

Polypeptides gdf15 pour le traitement et la prévention de maladies auto-immunes Download PDF

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Publication number
WO2023154953A1
WO2023154953A1 PCT/US2023/062564 US2023062564W WO2023154953A1 WO 2023154953 A1 WO2023154953 A1 WO 2023154953A1 US 2023062564 W US2023062564 W US 2023062564W WO 2023154953 A1 WO2023154953 A1 WO 2023154953A1
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polypeptide
gdf15
amino acid
seq
instances
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Zhiming Chen
Jer-Yuan HSU
Varun KAPOOR
Jonathan SITRIN
Jade BOJKOVIC
Igor MIKAELIAN
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NGM Biopharmaceuticals Inc
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NGM Biopharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

  • GDF15 POLYPEPTIDES FOR TREATING AND PREVENTING
  • the present invention relates to, in part, methods of treating and preventing autoimmune disorders, said methods comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a growth differentiation factor 15 (GDF15) polypeptide.
  • a subject e.g., a human
  • GDF15 growth differentiation factor 15
  • Autoimmune diseases are diseases in which a subject’s immune system mistakenly attacks the subject’s body. Normally, the immune system guards against foreign invaders such as bacteria and viruses. However, in autoimmune diseases the immune system mistakenly identifies the subject’s own cells as foreign invaders and mounts an immune response against the subject itself. Autoimmune diseases can be debilitating conditions, associated with pain, limitation of movement, and in some cases, loss of autonomy. Autoimmune diseases affect over 50 million Americans.
  • Wild type GDF15 also known as MIC-1 (macrophage inhibitory cytokine- 1) has been linked to regulation of body weight (Tsai VW, et al., PLoS One 2013; 8 (2): e55174; US 8,192,735).
  • Autoimmune diseases are diseases in which a subject's immune system mistakenly attacks the subject's body. Normally, the immune system guards against foreign invaders such as bacteria and viruses. However, in autoimmune diseases the immune system mistakenly identifies the subject's own cells as foreign invaders and mounts an immune response against the subject itself. There is an unmet need for advances in treatments for autoimmune diseases.
  • a GDF15 polypeptide is capable of suppressing the onset and/or progression of autoimmune diseases.
  • a GDF15 polypeptide is capable of suppressing the onset and/or progression of autoimmune diseases.
  • Both prophylactic and therapeutic administration of a GDF15 polypeptide attenuated autoimmune diseases, such as MS, inflammatory bowel disease, and type I diabetes in animal models.
  • Administration of the GDF15 polypeptide blocked pathogenic immune cell infiltration in the central nervous system in an animal model of MS and modulated the immune cell profile.
  • GDF15/glial cell derived neurotrophic factor family receptor alpha like (GFRAL) pathway mediated the role of GDF15 in attenuating autoimmune diseases.
  • GFRAL glial cell derived neurotrophic factor family receptor alpha like
  • an autoimmune disease e.g., MS
  • a subject e.g., a human
  • the method comprising: administering to the subject a therapeutically effective amount of a GDF15 polypeptide.
  • the GDF15 polypeptide binds GFRAL and activates GFRAL.
  • the autoimmune disease is MS.
  • the autoimmune disease is relapsing-remitting MS.
  • the autoimmune disease is primary progressive MS.
  • the autoimmune disease is secondary progressive MS.
  • the autoimmune disease is benign MS, primary progressive MS, secondary progressive MS, or relapsing-remitting MS.
  • the autoimmune disease is selected from the group consisting of MS, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), polymyositis, dermatopolymyositis, Addison's disease, Graves' disease, Sjogren's syndrome, Hashimoto's thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, scleroderma, cytokine release syndrome, and celiac disease.
  • the autoimmune disease is not a glucose metabolism disorder.
  • the autoimmune disorder is not type 1 diabetes.
  • an autoimmune disease e.g., MS
  • a subject e.g., a human
  • the method comprising: administering to the subject a therapeutically effective amount of a GDF15 polypeptide.
  • the GDF15 polypeptide binds GFRAL and activates GFRAL.
  • the autoimmune disease is MS.
  • the autoimmune disease is relapsing-remitting MS.
  • the autoimmune disease is primary progressive MS.
  • the autoimmune disease is secondary progressive MS.
  • the autoimmune disease is benign MS, primary progressive MS, secondary progressive MS, or relapsing-remitting MS.
  • the autoimmune disease is selected from the group consisting of MS, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), polymyositis, dermatopolymyositis, Addison's disease, Graves' disease, Sjogren's syndrome, Hashimoto's thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, scleroderma, cytokine release syndrome, and celiac disease.
  • MS systemic lupus erythematosus
  • CLE cutaneous lupus erythematosus
  • DLE discoid lupus erythematosus
  • the autoimmune disease is not a glucose metabolism disorder. In some instances, the autoimmune disorder is not type 1 diabetes.
  • Also provided herein is method for slowing down the onset of an autoimmune disease (e.g., MS) (e.g., slowing down the onset of one or more symptoms of an autoimmune disease) in a subject (e.g., a human) in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a GDF15 polypeptide, wherein the subject is at risk of developing the autoimmune disease.
  • the GDF15 polypeptide binds GFRAL and activates GFRAL.
  • the autoimmune disease is MS.
  • the autoimmune disease is relapsing-remitting MS. In some instances, the autoimmune disease is primary progressive MS. In some instances, the autoimmune disease is secondary progressive MS. In some instances, the autoimmune disease is benign MS, primary progressive MS, secondary progressive MS, or relapsing-remitting MS.
  • the autoimmune disease is selected from the group consisting of MS, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), polymyositis, dermatopolymyositis, Addison's disease, Graves' disease, Sjogren's syndrome, Hashimoto's thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, scleroderma, cytokine release syndrome, and celiac disease.
  • the autoimmune disease is not a glucose metabolism disorder.
  • the autoimmune disorder is not type 1 diabetes.
  • a method of reducing or blocking pathogenic immune cell infiltration into the central nervous system of a subject comprising administering to the subject a therapeutically effective amount of a GDF15 polypeptide.
  • the pathogenic immune cell is a pathogenic T cell.
  • the T cell is a CD4+ T cell.
  • the T cell is a Th- 17 cell.
  • the T cell is a Th-1 cell.
  • the T cell is a myelin oligodendrocyte glycoprotein (MOG)-specific CD4+ T cell.
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer; wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide; wherein the first polypeptide comprises from the N-terminus to the C- terminus a first human IgGl Fc domain , a linker, and a GDF15 mutein, wherein the first human IgGl Fc domain comprises a first hinge region, a first CH2 domain, and a first CH3 domain; wherein the second polypeptide comprises from the N-terminus to the C-terminus a second human IgGl Fc domain, wherein the second human IgGl Fc domain comprises a second hinge region, a second CH2 domain, and a second CH3 domain; and wherein the GDF15 polypeptide binds to GFRAL.
  • the first human IgGl Fc domain comprises an engineered protuberance and the second human IgGl Fc domain comprises an engineered cavity.
  • the engineered protuberance comprises at least one substitution of the corresponding amino acid in a human IgGl Fc sequence selected from the group consisting of amino acid residues 347, 366 and 394, according to EU numbering; and the engineered cavity comprises at least one substitution of the corresponding amino acid in a human IgGl Fc sequence selected from the group consisting of consisting of amino acid residues 366, 368, 394, 405, and 407, according to EU numbering.
  • the engineered protuberance comprises at least one substitution of the corresponding amino acid in a human IgGl Fc sequence selected from the group consisting of Q347W/Y, T366W/Y. and T394W/Y. according to EU numbering; and the engineered cavity comprises at least one substitution of the corresponding amino acid in a human IgGl Fc sequence selected from the group consisting of T366S, L368A, T394S, F405I7V/A, and Y407I7V/A, according to EU numbering.
  • the engineered protuberance comprises the substitution T366W, according to EU numbering, and wherein the engineered cavity comprises the substitutions T366S, L368A, and Y407V, according to EU numbering.
  • the engineered protuberance comprises the substitution T366Y, according to EU numbering, and wherein the engineered cavity comprises the substitution Y407T, according to EU numbering.
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:3-12. In some instances, the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:3. In some instances, the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3. In some instances, the GDF15 mutein consists of the amino acid sequence of SEQ ID NO:3.
  • the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13 or 14. In some instances, the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13. In some instances, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13. In some instances, the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the GDF15 polypeptide comprises a GDF15 mutein, wherein the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence the amino acid sequence of any one of SEQ ID NOs:3-12.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:7.
  • the GDF15 mutein consists of the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a GDF15 mutein comprising a contiguous amino acid sequence that is at least 90% identical to the amino acid sequence of wild type GDF15 (SEQ ID NO: 1). In some instances, the GDF15 mutein comprises at least one substitution of the corresponding amino acid in SEQ ID NO: 1 that creates the N-linked glycosylation consensus site. In some instances, the GDF15 mutein comprises at least one pair of substitutions of the corresponding amino acids in SEQ ID NO: 1 selected from the group consisting of: (i) K91N and D93T, (ii) K91N and D93S, (iii) D93N and G95T, or (iv) D93N and G95S. In some instances, the GDF15 mutein comprises an N-terminal deletion of one or more amino acids relative to the amino acid sequence of SEQ ID NO: 1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence the amino acid sequence of any one of SEQ ID NOs:3-12, wherein the first polypeptide is identical to the second polypeptide.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the subject is a human.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS. In some instances, the MS is secondary progressive MS.
  • the human subject is at risk of developing MS.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS. In some instances, the MS is secondary progressive MS.
  • Also provided herein is a method of treating MS in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a GDF15 polypeptide, wherein the GDF15 polypeptide consists of a dimer, wherein the dimer consists of a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the human subject is at risk of developing MS.
  • the MS is relapsingremitting MS.
  • the MS is primary progressive MS. In some instances, the MS is secondary progressive MS.
  • the GDF15 polypeptide comprises AMG 171. In some instances of the foregoing methods, the GDF15 polypeptide comprises LY3463251. In some instances of the foregoing methods, the GDF15 polypeptide comprises NN9215. In some instances of the foregoing methods, the GDF15 polypeptide comprises CIN-109.
  • EAE experimental autoimmune encephalomyelitis
  • FIG. 2 is a pair of graphs showing body weight (left) and body weight changes (right) of mice at the indicated time (days post immunization) as described in FIG. 1.
  • FIG. 4 is a graph showing the EAE score at the indicated time (days post immunization) induced by MOG35-55 immunization in C57BL/6 mice administered on day -2, 5, and 12 with 0.3 mg/kg anti-KLH antibody, 0.03 mg/kg of GDF15 Analog 1, 0.1 mg/kg of GDF15 Analog 1, or 0.3 mg/kg of GDF15 Analog 1.
  • FIG. 5 is a graph showing the EAE score at the indicated time (days post immunization) induced by MOG35-55 immunization in C57BL/6 mice. Mice were administered prophylactically (on day -2, 6, and 13) with 3 mg/kg anti-KLH antibody or 1 mg/kg of GDF15 Analog 1, or administered therapeutically (on day 12) with 3 mg/kg of GDF15 Analog 1.
  • FIG. 6A depicts representative FACS plots of Thl7 (T-helper 17) cells within the spinal tissue from the mice of Group 1 (left), Group 4 (middle), and Group 5 (right) as described in FIG. 1.
  • Y-axis cluster of differentiation 4 (CD4)
  • X-axis retinoic acid receptor-related orphan receptor gamma t (RORgt).
  • FIG. 6B is a pair of graphs showing the relative proportion (left) and absolute numbers (right) of Thl7 cells (RORgt CD4+ T cells) within the spinal tissue for the mice of Group 1, Group 4, and Group 5 as described in FIG. 1.
  • FIG. 7A depicts representative FACS plots of CD45 expressing cells within the spinal tissue from the mice of Groups 1 and 4-6 as described in FIG. 1.
  • Y- axis L-D (Live-Dead);
  • X-axis cluster of differentiation 45 (CD45) expression.
  • CD45hi marks all leukocytes.
  • CD45mid marks microglia.
  • FIG. 7B is a pair of graphs showing the relative proportion (left) and absolute numbers (right) of leukocytes (CD45hi cells) within the spinal tissue for the mice of Group 1, Group 4, and Group 5 as described in FIG. 1.
  • FIG. 8A depicts representative FACS plots of CD4+T cells within the spinal tissue from the mice of Groups 1 and 4-6 as described in FIG. 1.
  • Y-axis CD45
  • X-axis CD4.
  • FIG. 8B is a pair of graphs showing the relative proportion (left) and absolute numbers (right) of CD4+ T cells within the spinal tissue for the mice of Group 1, Group 4, and Group 5 as described in FIG. 1.
  • FIG. 9A depicts representative FACS plots of MOG-specific CD4+ T cells within the spinal tissue from the mice of Groups 1 and 4-6 as described in FIG. 1.
  • Y-axis CD4
  • X-axis MOG35-55 Tetramer.
  • FIG. 9B is a pair of graphs showing the relative proportion (left) and absolute numbers (right) of MOG-specific T cells within the spinal tissue for the mice of Group 1, Group 4, and Group 5 as described in FIG. 1.
  • FIG. 10 is a graph showing the EAE score of mice at the indicated days post receiving immune cells from donor mice.
  • Lymphocytes (from lymph nodes) and spleen cells from the mice were isolated (on day -3) and cultured ex vivo with anti-IL4 and IL12 for three days before being injected intraperitoneally into the recipient C57BL/6 mice.
  • FIG. 11 is a graph showing the EAE score of mice at the indicated days post receiving immune cells from donor mice.
  • the donor C57BL/6 mice were immunized with MOG35-55 (on day -14).
  • the lymphocytes (from lymph nodes) and spleen cells were isolated (on day -3) from the mice, and cultured ex vivo with anti- IL4 and IL12 for three days before being injected intraperitoneally into the recipient C57BL/6 mice.
  • the recipient mice were administered with 1 mg/kg anti-KLH or GDF15 Analog 1 at day 10, 17, and 24 post immune cell transfer.
  • FIG. 12 is a graph showing the EAE score in mice immunized with human MOG protein (1-120) at the indicated time. Mice were administered with control, 1 mg/kg GDF15 Analog 1, or anti-CD20 (lOOpg) weekly starting on day 7 post immunization with the human MOG protein.
  • FIG. 14 is a pair of graphs depicting the spleen weight (left) and spleen/body weight ratio (right) in a mouse model of inflammatory bowel disease (IBD), wherein CD4+ naive T cells from Balb/c donor mice were injected intraperitoneally into SCID Balb/c recipient mice. GDF15 Analog 1 or controls were administered weekly starting from the day of T cell transfer. Tissues were harvest and weighted at day 44 after cell transfer.
  • IBD inflammatory bowel disease
  • FIG. 15 shows the colon length (left), the colon weight (middle), and the colon weight/colon length ratio (right) of the mice as described in FIG.14
  • FIG. 16A is representative images of hematoxylin and eosin staining of longitudinal colon sections from the mice as described in FIG14.
  • the arrows illustrate the length defined as the thickness of the colonic epithelium.
  • FIG. 16B is a graph illustrating the sum of the averaged mucosal thickness in proximal, mid, and distal colon (pm) of the mice as described in FIG. 14
  • FIG. 17 is a pair of graphs showing the body weight (BW, gram) and body weight changes of SCID Balb/c mice at the indicated days post receiving CD4+ naive T cells from donor Balb/c mice as described in FIG.14.
  • FIG. 18 is a pair of graphs depicting the blood glucose level (mg/dL) (top) and the percentage of diabetes-free mice (bottom) at the indicated age (weeks) in the spontaneous type 1 diabetes NOD mouse model. 6-week old female NOD mice were administered once weekly with 1 mg/kg anti-KLH, 0.1 mg/kg GDF15 Analog 1, or 1 mg/kg GDF15 Analog 1. Diabetes was called when a mouse with blood glucose exceeding 250 mg/dL for two consecutive weeks.
  • FIG. 19 is a pair of graphs showing the body weight (top) and body weight changes (bottom) of mice at the indicated age as described in FIG. 18.
  • FIG. 20A is representative images of Luxol fast blue (LFB) staining (left) and IBA1 staining (right) of brain areas containing the corpus callosum from mice fed with 0.2% cuprizone (CPZ) diet for 3 or 5 weeks and being concomitantly administered with 0.3 mg/kg anti-KLH or GDF15 Analog 1 weekly.
  • LLB Luxol fast blue
  • CPZ cuprizone
  • FIG. 20B is a pair of graphs showing the quantification (mean +/- SEM) of LFB staining (left) and IBA1 staining (right) in corpus callosum from mice as described in FIG. 19A. Higher LFB grade shows more severe loss myelin sheath. * indicates p ⁇ 0.05.
  • FIG. 21 is a graph depicting the quantification (mean +/- SEM) of IBA1 staining in hippocampus from mice as described in FIG. 20A. * indicates p ⁇ 0.05, *** indicates p ⁇ 0.001.
  • FIG. 22 is a pair of graphs showing the quantification (mean +/- SEM) of GFAP staining in corpus callosum (left) or cortex (right) from mice as described in FIG. 19A. * indicates p ⁇ 0.05, **** indicates pO.OOOl.
  • FIG. 23 is a pair of graphs showing the quantification (mean +/- SEM) of LFB grade (left) and IBA1 staining (right) in the corpus callosum of mice that were fed with 0.2% CPZ-containing diet for 5 weeks followed by 2 weeks of normal chow to allow for remyelination.
  • CPZ + anti-KLH group and CPZ + GDF15 Analog 1 (Prophylactic, “Pro”) group received weekly dosing of anti-KLH or GDF15 Analog 1, respectively concomitant with the initiation of CPZ diet.
  • CPZ + GDF15 Analog 1 Therapeutic, “Ther” group received two weekly dosing of GDF15 Analog 1 at the onset of normal chow diet. * indicates p ⁇ 0.05, *** indicates p ⁇ 0.001.
  • FIG. 24 is a graph depicting the quantification (mean +/- SEM) of IB Al staining in hippocampus from mice as described in FIG. 22. ** indicates p ⁇ 0.01.
  • FIG. 25 is a pair of graphs showing the quantification (mean +/- SEM) of GFAP staining in corpus callosum (left) or cortex (right) from mice as described in FIG. 22. **** indicates pO.OOOl.
  • FIG. 26 is a graph showing EAE score at the indicated time induced by MOG35 -55 immunization in C57BL/6 mice.
  • Each of Img/kg of wild-type GDF15 and Img/kg of GDF15 Analog 2 was administered daily starting one day before the immunization.
  • 0.3 mg/kg anti-KLH antibody was used as a control.
  • GDF15 and a GDF15 analog is capable of immune suppression in autoimmune diseases.
  • Both prophylactic and therapeutic administration of a GDF15 analog attenuated autoimmune disease of the CNS in an animal model of MS.
  • Administration of the GDF15 analog blocked pathogenic immune cell infiltration in the central nervous system in an animal model of MS and modulated the immune cell profile.
  • the GDF15/GFRAL pathway mediated the role of GDF15 in attenuating autoimmune disease.
  • autoimmune diseases e.g., relapsing-remitting MS, primary progressive MS, secondary progressive MS.
  • a subject e.g., a human
  • the method comprising administering to the subject a therapeutically effective amount of a GDF15 polypeptide (or a pharmaceutical composition comprising the same).
  • the subject is at risk of developing the autoimmune disease.
  • Autoimmune diseases are diseases in which a subject’s immune system mistakenly attacks the subject’s body. Normally, the immune system guards against foreign invaders such as bacteria and viruses. However, in autoimmune diseases the immune system mistakenly identifies the subject’s own cells as foreign invaders and mounts an immune response against the subject itself.
  • Autoreactive T cells play an important effector role in the cell and tissue damage that encompasses autoimmune diseases, while under normal circumstances T cells maintain tolerance to self. Signs and symptoms of autoimmune diseases are known in the art, as are methods of diagnosing autoimmune diseases.
  • GDF15 polypeptides described herein can block infiltration of pathogenic immune cells into tissues. This is at least one mechanism via which GDF15 polypeptides can prevent or delay onset of autoimmune diseases, slow down progression of autoimmune diseases or treat autoimmune diseases.
  • Non-limiting examples of autoimmune diseases that can be treated according to the methods described herein include: MS, relapsing-remitting MS, primary progressive MS, secondary progressive MS, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), polymyositis, dermatopolymyositis, Addison’s disease, Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, scleroderma, cytokine release syndrome, and celiac disease.
  • the autoimmune disease is type 1 diabetes.
  • the autoimmune disease is type 1 diabetes.
  • the autoimmune disease is MS.
  • MS is an autoimmune disease of the CNS that affects over two million people.
  • MS is an immune-mediated inflammatory disease affecting brain, nerve, and spinal cord tissue which causes demyelination of neurons, axonal damage, and neurodegeneration.
  • CD4 (Thl, Thl7), CD8, and B cells are believed to play a role in MS.
  • the disease primarily affects white matter, but demyelination in gray matter also plays an important role. In most cases (>80%) the disease is relapsing/remitting.
  • the main symptoms of MS include CNS symptoms (e.g., fatigue, cognitive impairment, depression, anxiety, unstable mood), visual symptoms (e.g., nystagmus, optic neuritis, diplopia), speech symptoms (e.g., dysarthria), throat symptoms (e.g., dysphagia), musculoskeletal symptoms (e.g., weakness, spasms, ataxia), sensation symptoms (e.g., pain, hypoesthesias, paraesthesias), bowel symptoms (e.g., incontinence, diarrhea or constipation), and urinary symptoms (e.g., incontinence, frequency or retention).
  • CNS symptoms e.g., fatigue, cognitive impairment, depression, anxiety, unstable mood
  • visual symptoms e.g., nystagmus, optic neuritis, diplopia
  • speech symptoms e.g., dysarthria
  • throat symptoms e.g., dysphagia
  • musculoskeletal symptoms e.g., weakness, spasms
  • numbness or weakness in one or more limbs that typically occurs on one side of the body at a time, or your legs and trunk ; electric-shock sensations that occur with certain neck movements, especially bending the neck forward; tremor, lack of coordination or unsteady gait; partial or complete loss of vision, usually in one eye at a time, often with pain during eye movement; prolonged double vision; blurry vision; slurred speech; fatigue; dizziness; tingling or pain in parts of your body; and problems with sexual, bowel and bladder function.
  • the autoimmune disease is relapsing-remitting MS.
  • Relapsing-remitting MS is a type of MS where one has relapses followed by recovery and there is no new disability between attacks.
  • the autoimmune disease is primary progressive MS.
  • the autoimmune disease is secondary progressive MS.
  • Subjects may be genetically predisposed to develop an autoimmune disease. For instance, SLE and MS tend to run in families.
  • a subject is at risk of developing an autoimmune disease (e.g., MS) if one or more relatives (e.g., parent, sibling, grandparent, cousin, aunt, uncle) have been diagnosed with the autoimmune disease.
  • a subject is at risk of developing an autoimmune disease (e.g., MS) if the subject has one or more (e.g., 1, 2, 3, 4, 5) markers of the autoimmune disease (e.g., autoantibodies or genetic markers).
  • GDF15 polypeptides for use with the methods of treatment described herein.
  • GDF15 also known as MIC-1 (macrophage inhibitory cytokine- 1), PDF (prostate differentiation factor), PLAB (placental bone morphogenetic protein), NAG-1 (non-steroidal anti-inflammatory drugs (NSAIDs) activated gene), TGF-PL, and PTGFB, is a member of the transforming growth factor P (TGF- ) super-family.
  • Human GDF15 is synthesized as a 62 kDa intracellular precursor protein that is subsequently cleaved by a furin-like protease and is secreted as a 25 kDa disulfide-linked protein (see, e.g., Fairlie et al., J. Leukoc. Biol 65:2-5 (1999)).
  • GDF15 mRNA is seen in several tissues, including liver, kidney, pancreas, colon and placenta, and GDF15 expression in liver can be significantly up-regulated during injury of organs such as the liver, kidneys, heart and lungs.
  • the human GDF15 precursor is a 308 amino acid polypeptide (NCBI Ref. Seq.NP_004855.2; SEQ ID NO:2) containing a 29 amino acid signal peptide, a 167 amino acid pro-domain, and a mature domain of 112 amino acids which is excised from the pro-domain by furin-like proteases.
  • the human GDF15 precursor amino acid sequence referred to as “full-length” human GDF15 — is set forth in SEQ ID NO:2:
  • GDF15 residues refer to the 112 amino acid mature sequence (i.e., residue 1 is Ala (A), and residue 112 is He (I); see SEQ ID NO: 1).
  • residue 1 is Ala (A)
  • residue 112 is He (I); see SEQ ID NO: 1.
  • GDF15 precursor amino acid sequence predicts three excision sites, resulting in three putative forms of "mature" human GDF15 (i.e., 110, 112 and 115 amino acids)
  • the 112 amino acid mature sequence is accepted as being correct.
  • GDF15 orthologs and modified forms thereof, from other mammalian species, and their use, including mouse (NP_035949), chimpanzee (XP_524157), orangutan (XP_002828972), Rhesus monkey (EHH29815), giant panda (XP_002912774), gibbon (XP_003275874), guinea pig (XP_003465238), ferret (AER98997), cow (NP_001193227), pig (NP_001167527), dog (XP_541938) and platypus (Omithorhynchus anatinus;
  • variants of human GDF15 are encompassed by this disclosure. These variants may differ from SEQ ID NO:1 at 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid(s). These variants are still capable of being GDF15 agonists. In some instances, the variants able to bind GFRAL.
  • GDF15 polypeptides that are used in the methods of treatment and prevention described herein include all existing and known GDF15 proteins, homologues, muteins, fragments, modified forms thereof, fusion proteins, and analogues in the art. See, e.g., International Patent Application Publication Nos.
  • the GDF15 polypeptide comprises AMG 171. In some instance, the GDF15 polypeptide comprises LY3463251. In some instances, the GDF15 polypeptide comprises NN9215. In some instances, the GDF15 polypeptide comprises CIN-109.
  • the GDF15 polypeptides used herein retain one or more functions of wild-type GDF15.
  • the GDF15 polypeptides used herein bind GFRAL.
  • the GDF15 polypeptides activate GFRAL.
  • Methods of determining binding of a GDF15 polypeptide described herein are known in the art, such as, e.g., co-immunoprecipitation assays, ELISA assays, BIACORE, and co-immunofluorescence assays.
  • Methods of determining whether a GDF15 polypeptide described herein activates GFRAL are known in the art, such as, e.g., signaling reporter assays and detection of downstream signaling components.
  • the GDF15 polypeptides used herein exhibit at least 50% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100%) of the activity of wild type GDF15.
  • the GDF15 polypeptide used herein activates GFRAL to a level at least 50% of the level of GFRAL activation by wild type GDF15.
  • the GDF15 polypeptides used herein exhibit the same activity as wild type GDF15.
  • the GDF15 polypeptides used herein have an improved activity as compared to wild type GDF15, such as, e.g., increased solubility, increased stability, increased half-life, and/or increased expression yield compared to wild type GDF15.
  • the GDF15 polypeptide used herein have improved therapeutic efficacy compared to wild type GDF15 (e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% increased efficacy compared to wild type GDF15).
  • a GDF15 polypeptide used herein induces weight loss in an animal model.
  • the GDF15 polypeptides when administered into rodents (e.g., mice or rats) and/or non-human primates (e.g., cynomolgus monkeys), the GDF15 polypeptides are capable of inducing weight loss (e.g., a reduction in weight by at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% as compared to the weight prior to the administration).
  • the GDF15 polypeptide comprises wild type human GDF15 (SEQ ID NO: 1).
  • the GDF15 polypeptide comprises a GDF15 mutein.
  • GDF15 muteins are polypeptides comprising an artificially introduced change in the amino acid sequence of a wild type GDF15 (e.g., SEQ ID NO: 1), e.g., a change in amino acid sequence generated in the laboratory or other facility by human intervention (“hand of man”).
  • GDF15 muteins carry single or multiple (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions and/or deletions relative to the amino acid sequence of SEQ ID NO: 1.
  • a GDF15 mutein can be derived from a cloned gene (e.g., a wild type GDF15 gene) that has been subjected to site-directed or random mutagenesis, or from a completely synthetic gene.
  • a GDF15 mutein comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions and/or amino acid deletions relative to a reference polypeptide, e.g., relative to the amino acid sequence of SEQ ID NO: 1.
  • the GDF15 mutein has one or more substitutions at non-conserved residues in human GDF15 when it is aligned with one or more of its orthologs.
  • a GDF15 mutein comprises a contiguous amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1.
  • the GDF15 mutein includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions and/or deletions relative to the amino acid sequence of SEQ ID NO: 1.
  • the GDF15 mutein includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1.
  • the GDF15 mutein includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid deletions relative to the amino acid sequence of SEQ ID NO: 1. In some instances, the GDF15 mutein includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1 and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid deletions relative to the amino acid sequence of SEQ ID NO: 1. Modifications (e.g., substitutions, additions, and deletions) to GDF15 are well known in the art (see, e.g., International Patent Application Publication Nos.
  • the GDF15 muteins used in the methods described herein bind and activate GFRAL (e.g., human GFRAL). In some instances, the GDF15 mutein exhibits at least 50% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100%) of the activity of wild type GDF15.
  • GFRAL e.g., human GFRAL
  • the amino acid sequence of SEQ ID NO: 1 is used as a reference sequence for the GDF15 muteins presented herein. Therefore, the amino acid residue positions are numbered herein with reference to SEQ ID NO: 1.
  • the GDF15 mutein includes one, two, three or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, additions, and/or deletions that introduce one or more (e.g., 1, 2, 3, 4, 5) N-linked glycosylation consensus site(s) at a location where such a site is not present in SEQ ID NO: 1.
  • the N-linked glycosylation consensus site includes the sequence NXS/T, where N is Asn; X is an amino acid other than proline; followed by either Ser (S) or Thr (T). See, e.g., International Patent Application Publication Nos. WO 2016/069921 and WO 2016/018931, each of which is incorporated by reference herein in its entirety, for exemplary substitutions that introduce one or more N-linked glycosylation consensus site(s).
  • the GDF15 mutein comprises a contiguous amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 1, where the contiguous amino acid sequence has the substitution D5T/S or R21N.
  • the GDF15 mutein comprises a contiguous amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 1, where the contiguous amino acid sequence has at least one of the following pairs of substitutions relative to the corresponding amino acids in SEQ ID NO: 1: (i) R16N and H18T or R16N and H18S; (ii) S23N and E25T or S23N and E25S; (iii) L24N and D26T or L24N and D26S; (iv) S50N and F52T or S50N and F52S; (v) F52N and A54T or F52N and A54S; (vi) Q51N and R53T or Q51N and R53S; (vii) R53N and A55T or R53N and A55S; (viii) S64N and H66T or S64N
  • substitutions in (i) above denotes that the polypeptide has a threonine (T) or serine (S) at an amino acid position that corresponds to amino acid position 18 in SEQ ID NO:1, wherein in SEQ ID NO: 1 a histidine (H) is present at the amino acid position 18.
  • T threonine
  • S serine
  • H histidine
  • the position of the corresponding amino acid in a polypeptide relative to SEQ ID NO: 1 may be determined by aligning the amino acid sequences.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO: 1, except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions and/or deletions, optionally wherein one or more of the substitutions is selected from the following pairs of substitutions relative to the corresponding amino acids in SEQ ID NO:1 (i) R16N and H18T or R16N and H18S; (ii) S23N and E25T or S23N and E25S; (iii) L24N and D26T or L24N and D26S; (iv) S50N and F52T or S50N and F52S; (v) F52N and A54T or F52N and A54S; (vi) Q51N and R53T or Q51N and R53S; (vii) R53N and A55T or R53N and A55S; (viii) S64N and H66T or S64N and H66S; (ix) L65N and R67T or
  • the GDF15 mutein lacks the first amino acid of SEQ ID NO: 1. In some instances, the GDF15 mutein lacks the first two amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein lacks the first three amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein lacks the first six amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein lacks the first 14 amino acids of SEQ ID NO: 1.
  • the GDF15 mutein has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 3, except wherein the GDF15 mutein comprises a D5T/S substitution (relative to SEQ ID NO: 1) and lacks the first two amino acids of SEQ ID NO: 1.
  • the GDF15 mutein has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 5, except wherein the GDF15 mutein comprises a K91N substitution (relative to SEQ ID NO: 1) and a D93T/S substitution (relative to SEQ ID NO: 1).
  • the GDF15 mutein has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 5, except wherein the GDF15 mutein comprises a K91N substitution (relative to SEQ ID NO: 1), a D93T/S substitution (relative to SEQ ID NO: 1), and lacks the first three amino acids of SEQ ID NO: 1.
  • the GDF15 mutein has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 5, except wherein the GDF15 mutein comprises a D93N substitution (relative to SEQ ID NO: 1) and a G95T/S substitution (relative to SEQ ID NO: 1).
  • the GDF15 mutein has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 5, except wherein the GDF15 mutein comprises a D93N substitution (relative to SEQ ID NO: 1), a G95T/S substitution (relative to SEQ ID NO: 1), and lacks the first three amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein binds to GFRAL.
  • the present disclosure also includes GDF15 polypeptides that comprise active fragments (e.g., subsequences) of the GDF15 muteins described above.
  • the length of active fragments or subsequences may be 40 amino acids to 111 amino acids, e.g., 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98, 106, 109, or up to 111 amino acids.
  • Exemplary active fragments of the GDF15 muteins disclosed herein include GDF15 muteins that have deletions of amino acids (e.g., of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acids) relative to SEQ ID NO: 1.
  • the polypeptides may have N-terminal truncations and/or C-terminal truncations relative to SEQ ID NO: 1.
  • the truncations may be of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids relative to a reference polypeptide, e.g., SEQ ID NO: 1.
  • Truncated, active, forms of GDF15 are known in the art, see, e.g., International Patent Application Publication Nos. WO 2016/069921, WO 2016/018931, and WO 2014/120619, and US Patent Application Publication Nos.
  • the active fragment of the GDF15 mutein is lacking amino acid 1 of the amino acid sequence of SEQ ID NO: 1. In some instances, the active fragment of the GDF15 mutein is lacking amino acids 1 and 2 of the amino acid sequence of SEQ ID NO:1. In some instances, the active fragment of the GDF15 mutein is lacking amino acids 1 -3 of the amino acid sequence of SEQ ID NO: 1. In some instances, the active fragment of the GDF15 mutein is lacking amino acids 1-6 of the amino acid sequence of SEQ ID NO: 1. In some instances, the active fragment of the GDF15 mutein binds GFRAL.
  • the GDF15 muteins have a defined sequence identity compared to a reference sequence over a defined length of contiguous amino acids (e.g., a "comparison window").
  • Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci.
  • a GDF15 mutein can comprise an amino acid sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%, amino acid sequence identity to a contiguous stretch of 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or up to 112 amino acids in SEQ ID NO: 1.
  • the GDF15 mutein comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% amino acid sequence identity to the entire length of the amino acid sequence of SEQ ID NO: 1.
  • the GDF15 mutein is 112, 111, 110, 109, 108, 107, or 106 amino acids in length. In some instances, the GDF15 mutein is 112 amino acids in length. In some instances, the GDF15 mutein is 109 amino acids in length (e.g., lacks the first three amino acids of SEQ ID NO: 1). In some instances, the GDF15 mutein is 106 amino acids in length (e.g., lacks the first 6 amino acids of SEQ ID NO:1).
  • GDF15 in its active form is a dimer.
  • a GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein or wild type GDF15.
  • the first polypeptide is identical to the second polypeptide. In some instances, the first polypeptide is not identical to the second polypeptide.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein, e.g., a GDF15 mutein described herein.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence the amino acid sequence of any one of SEQ ID NOs:3-12.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions or deletions relative to the amino acid sequence of any one of SEQ ID NOs:3-10).
  • each of the first polypeptide and the second polypeptide lacks the first two amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first six amino acids of SEQ ID NO:1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7, wherein each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a wild type GDF15 or a GDF15 mutein attached to one or more molecules or moi eties. In some instances, the one or more molecules or moi eties extends the half-life of the GDF15 polypeptide.
  • the GDF15 polypeptide comprises a wild type GDF15 or a GDF15 mutein modified through, for example, pegylation (covalent attachment of one or more molecules of polyethylene glycol (PEG), or derivatives thereof); glycosylation (e.g., N-glycosylation); polysialylation; albumin fusion molecules comprising serum albumin (e.g., human serum albumin (HSA), cyno serum albumin, or bovine serum albumin (BSA)); albumin binding through, for example, a conjugated fatty acid chain (acylation); Fc-fusion; or fusion with a PEG mimetic.
  • pegylation covalent attachment of one or more molecules of polyethylene glycol (PEG), or derivatives thereof
  • glycosylation e.g., N-glycosylation
  • polysialylation e.g., albumin fusion molecules comprising serum albumin (e.g., human serum albumin (HSA), cyno serum albumin,
  • the GDF15 polypeptide comprises a wild type GDF15 or a GDF15 mutein linked to HSA as exemplified in US 2017/0327560, which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide is CIN-109.
  • the GDF15 polypeptide comprises a wild type GDF15 or a GDF15 mutein linked to a fatty acid chain, as exemplified in the Al, A2, or A3 formulae in WO 2015/200078, which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a wild type GDF15 or a GDF15 mutein, a N-terminal amino acid extensiON and a protractor, as exemplified in wo 2018/215525, which is incorporated by reference herein in its entirety.
  • the modifications are introduced in a site-specific manner.
  • the modifications include a linker. The linker may conjugate the modifying moiety to the polypeptide.
  • the GDF15 polypeptide comprises an Fc domain fused (either directly or indirectly, e.g., indirectly via a linker) to a GDF15 mutein or wild type GDF15, i.e., an Fc-GDF15 fusion polypeptide.
  • the Fc domain is from an IgG molecule (e.g., a human IgG moiety).
  • the human IgG Fc domain is from human IgGl, human IgG2, human IgG3, or human IgG4.
  • the Fc domain has reduced effector function or no effector function.
  • the Fc domain is a hinge-deleted Fc fragment, a charge-paired mutant of Fc fragment, a hinge deleted charge charge-paired Fc fragment, or a singlechain Fc fragment, as exemplified in Xiong et al., Sci. Transl. Med. 9, eaan8732 (2017), which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a GDF15 Fc fusion protein as exemplified in WO/2013/113008, which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide is AMG 171.
  • the GDF15 polypeptide is LY3463251 (see, e.g., Benichou et al., 2023, Cell Metabolism 35, 1- 13, which is incorporated by reference herein in its entirety).
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer, wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide; wherein the first polypeptide comprises a first IgG Fc domain (e.g., an IgGl Fc domain, an IgG2 Fc domain, an IgG3 Fc domain, an IgG4 Fc domain, e.g., a human IgGl Fc domain, a human IgG2 Fc domain, a human IgG3 Fc domain, a human IgG4 Fc domain) optionally a linker, and a GDF15 mutein or a wild type GDF15; wherein the second polypeptide comprises a second IgG Fc domain (e.g., an IgGl Fc domain, an IgG2 Fc domain, an IgG3 Fc domain, an IgG4 Fc domain)
  • the first IgG Fc domain comprises a human IgG Fc domain (e.g., a human IgGl Fc domain, a human IgG2 Fc domain, a human IgG3 Fc domain, a human IgG4 Fc domain).
  • the first and/or second IgG Fc domain has reduced or no effector function.
  • the first polypeptide in the first heterodimer dimerizes with the second polypeptide in the first heterodimer
  • the first polypeptide in the second heterodimer dimerizes with the second polypeptide in the second heterodimer
  • the GDF15 in the first heterodimer dimerizes with the GDF15 in the second heterodimer.
  • the first IgG Fc domain comprises a human IgGl Fc domain.
  • the second IgG Fc domain comprises a human IgG Fc domain (e.g., a human IgGl Fc domain, a human IgG2 Fc domain, a human IgG3 Fc domain, a human IgG4 Fc domain).
  • the second IgG Fc domain comprises a human IgGl Fc domain.
  • the first IgG Fc domain comprises a first hinge region, a first CH2 domain, and a first CH3 domain.
  • the second IgG Fc domain comprises a second hinge region, a second CH2 domain, and a second CH3 domain.
  • the first IgG Fc domain and the second IgG Fc domain have the same amino acid sequence as each other. In some instances, the first IgG Fc domain and the second IgG Fc domain have different amino acid sequences compared to each other. In some instances, the first IgG Fc domain is fused (e.g., directly or indirectly, e.g., indirectly via a linker) to the N-terminus of the GDF15 mutein or wild type GDF15. In some instances, the first IgG Fc domain is fused (e.g., directly or indirectly, e.g., indirectly via a linker) to the C-terminus of the GDF15 mutein or wild type GDF15.
  • the first IgG Fc domain is fused directly to the GDF15 mutein or wild type GDF15. In some instances, the first IgG Fc domain is fused to the GDF15 mutein or wild type GDF15 via a linker.
  • Linkers suitable for fusing an IgG Fc domain to a GDF15 mutein or wild type GDF15 are known in the art, see, e.g., the linkers disclosed in International Patent Application Publication No. WO 2016/069921 and US Patent Application Publication No. US 2016/0120999, each of which is incorporated by reference herein in its entirety.
  • the linker comprises the amino acid sequence (G4S)2 (SEQ ID NO: 18).
  • the linker comprises the amino acid sequence (G4S)s (SEQ ID NO: 19).
  • the linker comprises the amino acid sequence (G4S)s (SEQ ID NO:20).
  • the linker consists of the amino acid sequence of any one of SEQ ID NOs: 18-20.
  • IgG Fc domain sequence described herein or known in the art can be a component of a GDF15 polypeptide described herein.
  • the IgG Fc domain used in a GDF15 polypeptide described herein maintains the ability to bind to an Fc domain receptor when dimerized with another IgG Fc domain.
  • an IgG Fc domain is a human IgG Fc domain (e.g., a human IgGl, a human IgG2, a human IgG3, or a human IgG4) or a variant thereof (e.g., a human IgG Fc domain having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions and/or deletions while still maintaining the ability to bind to an Fc receptor when dimerized).
  • an IgG Fc domain is a human IgGl Fc domain.
  • the amino acid sequence of an exemplary human IgGl Fc domain is provided as SEQ ID NO: 16.
  • the numbering of the position of an amino acid in the Fc domain sequence is according to the EU numbering (Edelman, G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969)).
  • the glutamic acid residue "E” at position 1 in SEQ ID NO: 16 is numbered as 216; CH2 domain starts with alanine (A) which is numbered 231; CH3 domain starts at glycine (G) which is numbered 341, according to EU numbering.
  • an IgG Fc domain of a GDF15 polypeptide has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 16, wherein the IgG Fc domain binds to an Fc receptor.
  • an IgG Fc domain of a GDF15 polypeptide comprises the amino acid sequence of SEQ ID NO: 16 except having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 16, wherein the IgG Fc domain binds to an Fc receptor.
  • an IgG Fc domain of a GDF15 polypeptide is a fragment of an IgG Fc domain, wherein the fragment comprises a CH3 domain, wherein the fragment binds to an Fc receptor.
  • an IgG Fc domain of a GDF15 polypeptide is a fragment of an IgG Fc domain, wherein the fragment comprises a CH2 domain and a CH3 domain, wherein the fragment binds to an Fc receptor.
  • an IgG Fc domain of a GDF15 polypeptide is a fragment of an IgG Fc domain, wherein the fragment comprises a partial hinge region, CH2 domain and a CH3 domain, wherein the fragment binds to an Fc receptor.
  • an IgG Fc domain of a GDF15 polypeptide is a fragment of an IgG Fc domain, wherein the fragment comprises a hinge region, CH2 domain and a CH3 domain, wherein the fragment binds to an Fc receptor.
  • the CH3 domain has at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the CH3 domain of the amino acid sequence of SEQ ID NO: 16.
  • the CH2 domain has at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the CH2 domain of the amino acid sequence of SEQ ID NO: 16.
  • the hinge region has at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the hinge region of the amino acid sequence of SEQ ID NO: 16.
  • the partial hinge region has at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the partial hinge region of the amino acid sequence of SEQ ID NO: 16.
  • a first IgG Fc domain and a second IgG Fc domain of a GDF15 polypeptide are modified (relative to a corresponding wild type IgG Fc domain) to be partners of a charged Fc domain pair (see, e.g., International Patent Application Publication No. WO 2013/113008, which is incorporated by reference herein in its entirety).
  • All existing Fc heterodimerization technologies in the art can be used, including but not limited to steric complementary design, charge-to-charge swap design, charge-to-steric complementarity swap, long-range electrostatic interaction design, and isotype strand swap design (See, for example, Ha et al., Front. Immunol.
  • a first IgG Fc domain and a second IgG Fc domain of a GDF15 polypeptide are modified (relative to a corresponding wild type IgG Fc domain) to be partners of a protuberance/ cavity pair (also known in the art as a “knob/hole” pair) (see, e.g., the Fc domains and Fc domain substitutions disclosed in International Patent Application Publication No. WO 2016/069921 and US Patent Application Publication No. US 2016/0120999, each of which is incorporated by reference herein in its entirety).
  • the first IgG Fc domain comprises an engineered protuberance (also known in the art as a “knob”) and the second IgG Fc domain comprises an engineered cavity (also known in the art as a “hole”).
  • the first IgG Fc domain comprises an engineered cavity
  • the second IgG Fc domain comprises an engineered protuberance.
  • Exemplary protuberances and cavities are disclosed in US 8,216,805, which is incorporated by reference herein in its entirety, and include substitutions at the following amino acid positions: 347, 366, 368, 394, 405, and 407 according to the EU numbering. See, e.g., the Fc-GDF15 fusion polypeptides disclosed in International Patent Application Publication No.
  • the IgG Fc domain comprising an engineered protuberance comprises at least one (e.g., 1, 2, 3) substitution selected from the group consisting of Q347W/Y, T366W/Y, and T394W/Y according to the EU numbering.
  • the IgG Fc domain comprising an engineered cavity comprises at least one (e.g.
  • the IgG Fc domain comprising an engineered protuberance comprises the substitution T366W/Y according to the EU numbering and the IgG Fc domain comprising an engineered cavity comprises the substitutions T366S, L368A, and Y407I7V/A according to the EU numbering.
  • the IgG Fc domain comprising an engineered protuberance comprising the substitution T366W/Y according to the EU numbering and the IgG Fc domain comprising an engineered cavity comprises the substitution Y407T/V/A according to the EU numbering.
  • the IgG Fc domain comprising an engineered protuberance comprises the substitution T366Y according to the EU numbering and the IgG Fc domain comprising an engineered cavity comprises the substitution Y407T according to the EU numbering.
  • the IgG Fc domain comprising an engineered protuberance comprises the substitution T366W according to the EU numbering and the IgG Fc domain comprising an engineered cavity comprises the substitution Y407A according to the EU numbering.
  • the IgG Fc domain comprising an engineered protuberance comprises the substitution T394Y according to the EU numbering and the IgG Fc domain comprising an engineered cavity comprises the substitution Y407T according to the EU numbering.
  • the IgG Fc domain comprising an engineered protuberance comprises the substitution T366W according to the EU numbering and the IgG Fc domain comprising an engineered cavity comprises the substitutions T366S, L368A, and Y407V according to the EU numbering.
  • an IgG Fc domain of a GDF15 polypeptide comprises one or more (e.g., 1, 2, 3, 4, 5) mutation(s) that improve a property of the fusion polypeptide, e.g., reduction or abrogation of an IgG effector function such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cell phagocytosis (ADCP).
  • an IgG effector function such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cell phagocytosis (ADCP).
  • CDC complement-dependent cytotoxicity
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCP antibody-dependent cell phagocytosis
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer; wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide; wherein the first polypeptide comprises from the N-terminus to the C- terminus a first human IgGl Fc domain, a linker, and a GDF15 mutein, wherein the first human IgGl Fc domain comprises a first hinge region, a first CH2 domain, and a first CH3 domain; wherein the second polypeptide comprises from the N-terminus to the C-terminus a second human IgGl Fc domain, wherein the second human IgGl Fc domain comprises a second hinge region, a second CH2 domain, and a second CH3 domain; and wherein the GDF15 polypeptide binds to GFRAL.
  • the first human IgGl Fc domain comprises an engineered protuberance and the second human IgGl Fc domain comprises an engineered cavity.
  • the engineered protuberance comprises the substitution T366W according to the EU numbering and the engineered cavity comprises the substitutions T366S, L368A, and Y407V according to the EU numbering.
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:3-12 (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3-12, respectively, relative to SEQ ID NO: 1).
  • the GDF15 mutein comprises the amino acid sequence of any one of SEQ ID NOs:3-12 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3-12, respectively, relative to SEQ ID NO: 1).
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:3, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO:1 and lacks the first two amino acids of SEQ ID NO:1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO:1 and lacks the first two amino acids of SEQ ID NO:1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 and lacks the first two amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein consists of the amino acid sequence of SEQ ID NO:3. In some instances, the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13 or 14. In some instances, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 or 14 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions.
  • the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions relative to the amino acid sequence of SED ID NO: 13, except wherein the GDF15 mutein in SEQ ID NO: 13 comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO:1.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the complex binds to GFRAL.
  • the GDF15 polypeptide described herein comprises a GDF15 mutein or wild type GDF15 and hemiFc polypeptides (see, e.g., International Patent Application Publication NO. WO 2013/113008, which is incorporated by reference herein in its entirety).
  • the GDF15 polypeptide described herein retains one or more functions of wild type GDF15 (e.g., wild type human GDF15).
  • a GDF15 polypeptide described herein binds to GFRAL (e.g., human GFRAL) and/or mediates GDF15 signaling.
  • GFRAL e.g., human GFRAL
  • methods for determining the ability of a GDF15 polypeptide described herein to bind to GFRAL are known in the art, such as, e.g., radiolabeled antigen binding assay, Biacore, biolayer interferometry, enzyme-linked immunosorbent assay, immunohistochemistry, colocalization, co-immunoprecipitation, and signaling reporter assays (see, e.g., International Patent Application Publication No. WO 2017/172260, which is incorporated by reference herein in its entirety).
  • GDF15 signaling Methods for determining GDF15 signaling are known in the art, such as, e.g., ELK1 -luciferase reporter assays (see, e.g., International Patent Application Publication No. WO 2017/172260, which is incorporated by reference herein in its entirety).
  • the GDF15 polypeptide comprises a GDF15 polypeptide or a complex described in International Patent Application Publication No. WO 2016/069921 or in US Patent Application Publication No. US 2016/0120999, each of which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a GDF15 mutein, a modified GDF15 mutein, or a modified GDF15 described in International Patent Application Publication No. WO/2017/01893 lor in US Patent Application Publication No. US 2016/0031960, each of which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a GDF15 mutein, a modified GDF15 mutein, or a modified GDF15 described in International Patent Application Publication No. WO 2014/120619, in US Patent Application No. US 2014/0213511-Al, or in US Patent Application No. US 2016/0200787, each of which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a GDF15 mutein, a modified GDF15 mutein, or a modified GDF15 described in International Patent Application Publication No. WO 2013/148117 or in US Patent Application Publication No. US 2015/0023960, each of which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a fusion protein described in WO 2015/017710, which is incorporated by reference herein in its entirety. In some instances, the GDF15 polypeptide comprises a GDF15 polypeptide or construct comprising a GDF15 polypeptide described in WO 2013/113008, which is incorporated by reference herein in its entirety. In some instances, the GDF15 polypeptide comprises a GDF15 polypeptide described in WO 2012/138919, which is incorporated by reference herein in its entirety. In some instances, the GDF15 polypeptide comprises a GDF15 variant, a GDF15 fusion protein, or a GDF15 conjugate described in WO 2017/109706, which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a compound or homodimer described in US Patent Application Publication No. US 2019/030903 or International Publication No. W02019195091A1, each of which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a GDF15 molecule described in International Publication No. WO 2020/185533, which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptide comprises a GDF15 agonist identified using a screening assay described in International Publication No. WO/2018/071493, which is incorporated by reference herein in its entirety.
  • the GDF15 polypeptides described herein can be produced by any suitable method known in the art. Such methods range from direct protein synthesis methods to constructing a DNA sequence encoding polypeptide sequences and expressing those sequences in a suitable host. See, e.g., International Patent Application Publication No. WO 2016/069921, which is incorporated by reference herein in its entirety, for a description of various methods for producing GDF15 polypeptides.
  • the GDF15 polypeptide described herein is administered to a subject (e.g., human) as a pharmaceutical composition (e.g., a sterile pharmaceutical composition) in a method of treatment described herein.
  • a pharmaceutical composition e.g., a sterile pharmaceutical composition
  • pharmaceutical compositions comprising a GDF15 polypeptide described herein.
  • the pharmaceutical composition comprises: a GDF15 polypeptide, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are known in the art.
  • the pharmaceutical composition is a sterile pharmaceutical composition.
  • a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same can be used to treat an autoimmune disease (e.g., relapsingremitting MS, primary progressive MS, secondary progressive MS) in a subject (e.g., a human) in need thereof.
  • an autoimmune disease e.g., relapsingremitting MS, primary progressive MS, secondary progressive MS
  • a method for treating an autoimmune disease e.g., relapsing-remitting MS, primary progressive MS, secondary progressive MS
  • the method comprising administering to the subject (e.g., human) a therapeutically effective amount of a GDF15 polypeptide (or composition comprising the same) to the subject.
  • the autoimmune disease is relapsing-remitting MS. In some instances, the autoimmune disease is primary progressive MS. In some instances, the autoimmune disease is secondary progressive MS. In some cases, the MS is benign MS. In some instances, the autoimmune diseases is psoriasis, psoriatic arthritis, or an inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis). In some instances, the subject is a human.
  • a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same can be used to slow down progression of an autoimmune disease (e.g., MS) in a subject (e.g., a human) in need thereof.
  • an autoimmune disease e.g., MS
  • a method for slowing down progression of an autoimmune disease (e.g., MS) in a subject (e.g., a human) in need thereof comprising administering to the subject (e.g., human) a therapeutically effective amount of a GDF15 polypeptide (or composition comprising the same) to the subject.
  • the autoimmune disease is relapsing-remitting MS.
  • the autoimmune disease is primary progressive MS.
  • the autoimmune disease is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune diseases is psoriasis, psoriatic arthritis, or an inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the subject is a human.
  • the autoimmune disease is MS.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune diseases is selected from the group consisting of MS (e.g., relapsing-remitting MS, primary progressive MS, secondary progressive MS), rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), polymyositis, dermatopolymyositis, Addison’s disease, Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, scleroderma, cytokine release syndrome, and celiac disease.
  • MS e.g., relapsing-remitting MS, primary progressive MS, secondary progressive MS
  • the autoimmune disease is MS. In some cases, the MS is relapsing-remiting MS. In some cases, the MS is primary progressive MS. In some cases, the MS is secondary progressive MS. In some cases, the MS is benign MS. [00102] In some instances, the autoimmune disease is type 1 diabetes. In some instances, the autoimmune disease is not Type 1 diabetes. In some instances, the autoimmune disease is not a glucose metabolism disorder.
  • the method comprises administering to the subject a therapeutically effective amount of a GDF15 polypeptide (e.g., a GDF15 polypeptide described herein).
  • a GDF15 polypeptide e.g., a GDF15 polypeptide described herein.
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer; wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide; wherein the first polypeptide comprises from the N-terminus to the C- terminus a first human IgGl Fc domain, a linker, and a GDF15 mutein, wherein the first human IgGl Fc domain comprises a first hinge region, a first CH2 domain, and a first CH3 domain; wherein the second polypeptide comprises from the N-terminus to the C-terminus a second human IgGl Fc domain, wherein the second human IgGl Fc domain comprises a second hinge region, a second CH2 domain, and a second CH3 domain; and wherein the GDF15 polypeptide binds to GFRAL.
  • the first human IgGl Fc domain comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions that reduces or abrogates an Fc effector function (e.g., as described herein above).
  • the first human IgGl Fc domain comprises an engineered protuberance and the second human IgGl Fc domain comprises an engineered cavity.
  • the engineered protuberance comprises the substitution T366W according to the EU numbering and the engineered cavity comprises the substitutions T366S, L368A, and Y407V according to the EU numbering.
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:3-12 (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3-12, respectively, relative to SEQ ID NO: 1).
  • the GDF15 mutein comprises the amino acid sequence of any one of SEQ ID NOs:3-12 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3- 12, respectively, relative to SEQ ID NO: 1).
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:3, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 and lacks the first two amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein consists of the amino acid sequence of SEQ ID NO:3. In some instances, the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13 or 14. In some instances, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 or 14 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions.
  • the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions relative to the amino acid sequence of SED ID NO: 13, except wherein the GDF15 mutein in SEQ ID NO: 13 comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the complex binds to GFRAL.
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer, wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15; wherein the first heterodimer dimerizes with the second heterodimer.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13 and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the subject is a human.
  • the autoimmune disease is MS.
  • the MS is relapsingremitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune diseases is psoriasis, psoriatic arthritis, or an inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein or wild type GDF15.
  • the first polypeptide is identical to the second polypeptide.
  • the first polypeptide is not identical to the second polypeptide.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein, e.g., a GDF15 mutein described herein.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence the amino acid sequence of any one of SEQ ID NOs:3-12.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions or deletions relative to the amino acid sequence of any one of SEQ ID NOs:3-10).
  • each of the first polypeptide and the second polypeptide lacks the first two amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first six amino acids of SEQ ID NO: 1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7, wherein each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO:1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7, wherein each of the first polypeptide and second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the subject is a human.
  • the autoimmune disease is MS. In some cases, the MS is relapsing-remitting MS. In some cases, the MS is primary progressive MS. In some cases, the MS is secondary progressive MS. In some cases, the MS is benign MS. In some instances, the autoimmune diseases is psoriasis, psoriatic arthritis, or an inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the GDF15 polypeptides can be administered in any number of ways for either local or systemic delivery. Further, the GDF15 polypeptides (or pharmaceutical compositions comprising the same) used in the methods of treatment described herein can be administered to the subject in a therapeutically effective amount.
  • therapeutically effective amount refers to the amount of an agent (e.g., GDF15 polypeptide) that is sufficient to reduce and/or ameliorate the severity and/or duration of (i) a disease, disorder or condition in a subject, and/or (ii) a symptom in a subject.
  • the method of treating obtains a desired pharmacological and/or physiological effect in the subject being administered the GDF15 polypeptide.
  • the method of treating inhibits the autoimmune disease, e.g., arrests its development.
  • the method of treating relieves the autoimmune disease, e.g., causes a regression of the autoimmune disease.
  • the method of treating slows down progression of the autoimmune disease.
  • the method of treating prolongs survival of the subject administered the GDF15 polypeptide as compared to expected survival if not receiving the treatment.
  • the method of treating reduces one or more (e.g., 1, 2, 3, 4, 5) symptoms of the autoimmune disease.
  • the method of treating reduces one or more (e.g., 1, 2, 3, 4, 5) symptoms of MS.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS. Symptoms of MS and clinical endpoints for treatment of MS are known in the art (see, e.g., van Munster and Uitdehaag, CNS Drugs, 2017; 31(3):217-236, which is incorporated by reference herein in its entirety).
  • the method for treatment reduces (e.g., by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, or at least 50%, 10-50%, 10-25%, 10-15%, 25-50%, or 5-25%) infiltration of pathogenic immune cells into the tissues or organs (e.g., CNS) in the subject.
  • the reduction is compared to a level of pathogenic immune cells in the tissues or organs (e.g., CNS) prior to administration of the GDF15 polypeptide.
  • Methods for determining infiltration of pathogenic immune cells into the CNS are known in the art.
  • the GDF15 polypeptide is administered to the subject (e.g., human) as a pharmaceutical composition (e.g., a sterile pharmaceutical composition).
  • the pharmaceutical composition comprises: a GDF15 polypeptide, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are known in the art.
  • the pharmaceutical composition is a sterile pharmaceutical composition.
  • a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same can be used to prevent an autoimmune disease (e.g., MS) in a subject (e.g., a human) in need thereof.
  • an autoimmune disease e.g., MS
  • a method for preventing an autoimmune disease in a subject (e.g., a human) in need thereof comprising administering to the subject (e.g., human) a therapeutically effective amount of a GDF15 polypeptide (or composition comprising the same) to the subject.
  • the autoimmune disease is relapsing-remitting MS.
  • the autoimmune disease is primary progressive MS.
  • the autoimmune disease is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune diseases is psoriasis, psoriatic arthritis, or an inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the subject is a human.
  • a subject is at risk of developing an autoimmune disease if one or more relatives (e.g., parent, sibling, grandparent, cousin, aunt, uncle) of the subject have been diagnosed with the autoimmune disease.
  • a subject is at risk of developing an autoimmune disease if the subject has one or more markers of the autoimmune disease (e.g., autoantibodies or genetic marker(s).
  • the therapeutically effective amount of the GDF15 polypeptide is administered to the subject prior to onset of one or more symptoms of the autoimmune disease. In some instances, the therapeutically effective amount of the GDF15 polypeptide is administered to the subject prior to a diagnosis of the autoimmune disease in the subject. In some instances, the autoimmune disease is relapsing-remitting MS. In some instances, the autoimmune disease is primary progressive MS. In some instances, the autoimmune disease is secondary progressive MS. In some cases, the MS is benign MS. In some instances, the autoimmune diseases is psoriasis, psoriatic arthritis, or inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the autoimmune disease is MS.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune diseases is selected from the group consisting of MS (e.g., relapsing-remitting MS, primary progressive MS, secondary progressive MS), rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), polymyositis, dermatopolymyositis, Addison’s disease, Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, scleroderma, cytokine release syndrome, and celiac disease.
  • MS e.g., relapsing-remitting MS, primary progressive MS, secondary progressive MS
  • the autoimmune disease is MS. In some cases, the MS is relapsing-remitting MS. In some cases, the MS is primary progressive MS. In some cases, the MS is secondary progressive MS. In some cases, the MS is benign MS. [00119] In some instances, the autoimmune disease is type 1 diabetes. In some instances, the autoimmune disease is not Type 1 diabetes. In some instances, the autoimmune disease is not a glucose metabolism disorder.
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer; wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide; wherein the first polypeptide comprises from the N-terminus to the C- terminus a first human IgGl Fc domain, a linker, and a GDF15 mutein, wherein the first human IgGl Fc domain comprises a first hinge region, a first CH2 domain, and a first CH3 domain; wherein the second polypeptide comprises from the N-terminus to the C-terminus a second human IgGl Fc domain, wherein the second human IgGl Fc domain comprises a second hinge region, a second CH2 domain, and a second CH3 domain; and wherein the GDF15 polypeptide binds to GFRAL.
  • the first human IgGl Fc domain comprises an engineered protuberance and the second human IgGl Fc domain comprises an engineered cavity.
  • the engineered protuberance comprises the substitution T366W according to the EU numbering and the engineered cavity comprises the substitutions T366S, L368A, and Y407V according to the EU numbering.
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:3-12 (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3-12, respectively, relative to SEQ ID NO: 1).
  • the GDF15 mutein comprises the amino acid sequence of any one of SEQ ID NOs:3-12 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3-12, respectively, relative to SEQ ID NO: 1).
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:3, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO:1 and lacks the first two amino acids of SEQ ID NO:1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 and lacks the first two amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein consists of the amino acid sequence of SEQ ID NO:3. In some instances, the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13 or 14. In some instances, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 or 14 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions.
  • the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions relative to the amino acid sequence of SED ID NO: 13, except wherein the GDF15 mutein in SEQ ID NO: 13 comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the complex binds to GFRAL.
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer, wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15; wherein the first heterodimer dimerizes with the second heterodimer.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13 and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the subject is a human.
  • the autoimmune disease is MS.
  • the MS is relapsingremitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune diseases is psoriasis, psoriatic arthritis, or an inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein or wild type GDF15.
  • the first polypeptide is identical to the second polypeptide.
  • the first polypeptide is not identical to the second polypeptide.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein, e.g., a GDF15 mutein described herein.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence the amino acid sequence of any one of SEQ ID NOs:3-12.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions or deletions relative to the amino acid sequence of any one of SEQ ID NOs:3-10).
  • each of the first polypeptide and the second polypeptide lacks the first two amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first six amino acids of SEQ ID NO: 1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7, wherein each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO:1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7, wherein each of the first polypeptide and second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the subject is a human.
  • the autoimmune disease is MS.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune diseases is psoriasis, psoriatic arthritis, or an inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the GDF15 polypeptides (or pharmaceutical compositions comprising the same) can be administered in any number of ways for either local or systemic delivery. Further, the GDF15 polypeptides (or pharmaceutical compositions comprising the same) used in the methods of prevention described herein can be administered to the subject in a therapeutically effective amount.
  • the term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., GDF15 polypeptide) that is sufficient to reduce and/or ameliorate the severity and/or duration of (i) a disease, disorder or condition in a subject, and/or (ii) a symptom in a subject.
  • an agent e.g., GDF15 polypeptide
  • the method of prevention obtains a desired pharmacological and/or physiological effect in the subject being administered the GDF15 polypeptide.
  • the method of prevention inhibits the autoimmune disease, e.g., arrests its development or prolongs or delays its onset as compared to expected development or onset if not receiving the treatment.
  • the method of prevention prolongs survival of the subject administered the GDF15 polypeptide as compared to expected survival if not receiving the treatment.
  • the GDF15 polypeptides (or pharmaceutical compositions comprising the same) can be administered in any number of ways for either local or systemic prevention.
  • the GDF15 polypeptides (or pharmaceutical compositions comprising the same) used in the methods of prevention described herein can be administered to the subject in a therapeutically effective amount.
  • therapeutically effective amount encompasses an amount of an agent (e.g., GDF15 polypeptide) necessary for the (i) reduction or amelioration of the development, or onset of a given disease, disorder, or condition, and/or (ii) the improvement or enhancement of the prophylactic or therapeutic effect(s) of another agent or therapy (e.g., an agent other than the binding agents provided herein).
  • the method of prevention prevents or delays onset of one or more (e.g., 1, 2, 3, 4, 5) symptoms of the autoimmune disease.
  • the method is for preventing MS (e.g., benign MS, primary progressive MS, secondary progressive MS, relapsing-remitting MS)
  • the method of prevention prevents or delays onset of one or more (e.g., 1, 2, 3, 4, 5) symptoms of MS.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS. Symptoms of MS and clinical endpoints for treatment of MS are known in the art (see, e.g., van Munster and Uitdehaag, CNS Drugs, 2017; 31(3):217- 236, which is incorporated by reference herein in its entirety).
  • the method for prevention reduces (e.g., by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, or at least 50%, 10-50%, 10-25%, 10-15%, 25-50%, or 5-25%) infiltration of pathogenic immune cells into the tissues or organs (e.g., CNS) in the subject.
  • the reduction is compared to a level of pathogenic immune cells in the tissues or organs (e.g., CNS) prior to administration of the GDF15 polypeptide.
  • Methods for determining infiltration of pathogenic immune cells into the tissues or organs are known in the art. For example, for CNS biopsy lumbar puncture can be performed to obtain spinal tissue or spinal fluid, which is then tested for pathogenic immune cells and autoantibodies.
  • the GDF15 polypeptide is administered to the subject (e.g., human) as a pharmaceutical composition (e.g., a sterile pharmaceutical composition).
  • the pharmaceutical composition comprises: a GDF15 polypeptide, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are known in the art.
  • the pharmaceutical composition is a sterile pharmaceutical composition.
  • a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same can be used to reduce or block pathogenic immune cell infiltration into tissue(s) or organ(s) (e.g., CNS) of a subject suffering from an autoimmune disease.
  • a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same is used to reduce or block pathogenic immune cell infiltration into tissue(s) or organ(s) (e.g., CNS) of a subject suffering from relapsing-remitting MS.
  • a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same is used to reduce or block pathogenic immune cell infiltration into tissue(s) or organ(s) (e.g., CNS) of a subject suffering from primary progressive MS. In some instances, a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same is used to reduce or block pathogenic immune cell infiltration into tissue(s) or organ(s) (e.g., CNS) of a subject suffering from secondary progressive MS. In some instances, a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same is used to reduce or block pathogenic immune cell infiltration into one or more joints of a subject suffering from psoriatic arthritis.
  • a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same is used to reduce or block pathogenic immune cell infiltration into the skin, nails or joints of a subject suffering from psoriasis. In some instances, a GDF15 polypeptide described herein or a pharmaceutical composition comprising the same is used to reduce or block pathogenic immune cell infiltration into the digestive tract of a subject suffering from inflammatory bowel disease.
  • a method for reducing or blocking pathogenic immune cell infiltration into tissue(s) or organ(s) of a subject comprising administering to the subject (e.g., human) a therapeutically effective amount of a GDF15 polypeptide (or composition comprising the same) to the subject.
  • the autoimmune disease is relapsing-remitting MS.
  • the autoimmune disease is primary progressive MS.
  • the autoimmune disease is secondary progressive MS.
  • the autoimmune disease is benign MS.
  • the autoimmune disease is psoriasis, psoriatic arthritis, or inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
  • the autoimmune disease is type 1 diabetes.
  • the autoimmune disease is not Type 1 diabetes.
  • the autoimmune disease is not a glucose metabolism disorder.
  • the subject is a human.
  • the pathogenic immune cell is a pathogenic T cell.
  • the T cell is a CD4+ T cell.
  • the T cell is a Th-1 cell.
  • the T cell is a Th-17 cell.
  • the T cell is a myelin oligodendrocyte glycoprotein (MOG)-specific CD4+ T cell.
  • MOG myelin oligodendrocyte glycoprotein
  • Methods for determining infiltration of pathogenic immune cells into tissues and organs are known in the art. For example, to determine infiltration into the CNS, a biopsy can be taken via lumbar puncture to obtain spinal tissue or spinal fluid, which is then tested for pathogenic immune cells and autoantibodies.
  • the subject has an autoimmune disease.
  • the autoimmune disease is MS.
  • the MS is relapsingremitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the MS is benign MS.
  • the autoimmune disease is selected from the group consisting of MS, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), polymyositis, dermatopolymyositis, Addison’s disease, Graves’ disease, Sjogren’s syndrome, Hashimoto’s thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, scleroderma, cytokine release syndrome, and celiac disease.
  • SLE systemic lupus erythematosus
  • CLE cutaneous lupus erythematosus
  • DLE discoid lupus erythematos
  • the autoimmune disease is MS. In some cases, the MS is relapsing-remitting MS. In some cases, the MS is primary progressive MS. In some cases, the MS is secondary progressive MS. In some cases, the MS is benign MS. [00136] In some instances, the autoimmune disease is type 1 diabetes. In some instances, the autoimmune disease is not Type 1 diabetes. In some instances, the autoimmune disease is not a glucose metabolism disorder.
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer; wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide; wherein the first polypeptide comprises from the N-terminus to the C- terminus a first human IgGl Fc domain, a linker, and a GDF15 mutein, wherein the first human IgGl Fc domain comprises a first hinge region, a first CH2 domain, and a first CH3 domain; wherein the second polypeptide comprises from the N-terminus to the C-terminus a second human IgGl Fc domain, wherein the second human IgGl Fc domain comprises a second hinge region, a second CH2 domain, and a second CH3 domain; and wherein the GDF15 polypeptide binds to GFRAL.
  • the first human IgGl Fc domain comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions that reduces or abrogates an Fc effector function (e.g., as described herein above).
  • the first human IgGl Fc domain comprises an engineered protuberance and the second human IgGl Fc domain comprises an engineered cavity.
  • the engineered protuberance comprises the substitution T366W according to the EU numbering and the engineered cavity comprises the substitutions T366S, L368A, and Y407V according to the EU numbering.
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:3-12 (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3-12, respectively, relative to SEQ ID NO:1).
  • the GDF15 mutein comprises the amino acid sequence of any one of SEQ ID NOs:3-12 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions (except wherein the GDF15 mutein retains the one or more differences in any one of SEQ ID NOs:3- 12, respectively, relative to SEQ ID NO:1).
  • the GDF15 mutein comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:3, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions, except wherein the GDF15 mutein comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the GDF15 mutein comprises the amino acid sequence of SEQ ID NO:3 and lacks the first two amino acids of SEQ ID NO: 1. In some instances, the GDF15 mutein consists of the amino acid sequence of SEQ ID NO:3. In some instances, the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13 or 14. In some instances, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 or 14 except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions.
  • the first polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions relative to the amino acid sequence of SED ID NO: 13, except wherein the GDF15 mutein in SEQ ID NO: 13 comprises a D5T/S substitution relative to SEQ ID NO: 1 and lacks the first two amino acids of SEQ ID NO: 1.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the complex binds to GFRAL.
  • the GDF15 polypeptide comprises a complex comprising a first heterodimer and a second heterodimer, wherein each of the first heterodimer and the second heterodimer comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 15; wherein the first heterodimer dimerizes with the second heterodimer.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13.
  • the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13 and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15.
  • the subject is a human.
  • the autoimmune disease is MS. In some instances, the MS is relapsingremitting MS. In some instances, the MS is primary progressive MS. In some instances, the MS is secondary progressive MS. In some cases, the MS is benign MS. In some instances, the autoimmune disease is psoriasis, psoriatic arthritis, or inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis). In some instances, the autoimmune disease is type 1 diabetes. In some instances, the autoimmune disease is not Type 1 diabetes. In some instances, the autoimmune disease is not a glucose metabolism disorder.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein or wild type GDF15.
  • the first polypeptide is identical to the second polypeptide.
  • the first polypeptide is not identical to the second polypeptide.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises a GDF15 mutein, e.g., a GDF15 mutein described herein.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence the amino acid sequence of any one of SEQ ID NOs:3-12.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises an amino acid sequence having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) substitutions or deletions relative to the amino acid sequence of any one of SEQ ID NOs:3-10).
  • each of the first polypeptide and the second polypeptide lacks the first two amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide lacks the first six amino acids of SEQ ID NO: 1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7, wherein each of the first polypeptide and the second polypeptide lacks the first three amino acids of SEQ ID NO:1.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the GDF15 polypeptide comprises a dimer, wherein the dimer comprises a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide comprises the amino acid sequence of SEQ ID NO:7, wherein each of the first polypeptide and second polypeptide lacks the first three amino acids of SEQ ID NO: 1.
  • each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO:7.
  • the subject is a human.
  • the autoimmune disease is MS.
  • the MS is relapsing-remitting MS.
  • the MS is primary progressive MS.
  • the MS is secondary progressive MS.
  • the autoimmune disease is benign MS. In some instances, the autoimmune disease is psoriasis, psoriatic arthritis, or inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis). In some instances, the autoimmune disease is type 1 diabetes. In some instances, the autoimmune disease is not Type 1 diabetes. In some instances, the autoimmune disease is not a glucose metabolism disorder.
  • the GDF15 polypeptides can be administered in any number of ways for either local or systemic delivery. Further, the GDF15 polypeptides (or pharmaceutical compositions comprising the same) used in the methods reducing or blocking pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of a subject described herein can be administered to the subject in a therapeutically effective amount.
  • the term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., GDF15 polypeptide) that is sufficient to reduce and/or block pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of the subject.
  • the method of reducing or blocking pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of a subject reduces or blocks the pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of the subject by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100 % as compared to pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of a subject suffering from an autoimmune disease and not receiving the GDF15 polypeptide.
  • the method of reducing or blocking pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of a subject reduces or blocks the pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of the subject by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100 % as compared to pathogenic immune cell infiltration into the tissue(s) or organ(s) (e.g., CNS) of the subject prior to (e.g., within 1 day, within 1 week, within 1 month) being administered the GDF15 polypeptide.
  • the GDF15 polypeptide is administered to the subject (e.g., human) as a pharmaceutical composition (e.g., a sterile pharmaceutical composition).
  • the pharmaceutical composition comprises: a GDF15 polypeptide, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are known in the art.
  • the pharmaceutical composition is a sterile pharmaceutical composition.
  • EAE Experimental autoimmune encephalomyelitis
  • EAE Experimental autoimmune encephalomyelitis
  • MOG/CFA emulsion in prefilled syringes were injected subcutaneously on two sites dorsally, 0.1 mL/site (0.2 mL/mouse total) with a total of 0.2 mg of MOGss-sspeptide.
  • mice were injected intraperitoneally with 85-110 ng of pertussis toxin (PTX) at 4 hours and then 1 day post MOG injection.
  • PTX pertussis toxin
  • mice For prophylactic GDF15 ANALOGS treatment in C57BL/6 mice, the protein was injected subcutaneously 1-2 days prior to MOG immunization followed by weekly subcutaneous injection. In some studies, the mice were sacrificed at day 16 after MOG immunization and their inguinal lymph nodes, spleen and spinal cords harvested for FACS analyses. For therapeutic treatment, GDF15 ANALOGS were injected 7-10 days post immunization when at least 20% of mice reached EAE score of 0.5-l.
  • mice Female C57BL/6 mice around 22 grams and approximately 16 weeks old (The Jackson Laboratory, ME, USA) were used. The animals were kept under a 12- hour-light/dark cycle under controlled temperature (22 ⁇ 2°C) and humidity (50% ⁇ 20%) with access to food and water ad libitum. [00148] EAE in these mice were induced by using the MOG1-125/CFA Emulsion PTX kit (EK-2160, Hooke Laboratories, Lawrence, MA, USA).
  • mice Female SJL mice around 20 grams and approximately 8 weeks old (The Jackson Laboratory, ME, USA) were used. The animals were kept under a 12-hour- light/dark cycle under controlled temperature (22 ⁇ 2°C) and humidity (50% ⁇ 20%) with access to food and water ad libitum.
  • EAE in these mice were induced by using the [Serl40]-PLP 139-151/CFA Emulsion kit (EK0120, Hooke Laboratories, Lawrence, MA, USA). Sequence HSLGKWLGHPDKF (SEQ ID NO: 25). PLP139-151 emulsion prefilled syringes were injected subcutaneously on four sites dorsally, 0.05 mL/site (0.2 mL/mouse total) with a total of 0.1 mg of PLP139-151 peptide.
  • the digested single cell suspension was filtered and transferred to a tube with 5 mL RPMI + 2% fetal bovine serum (FS) and centrifuged for 5 minutes at 1300 revolutions per minute (rpm) at 4 °C. Supernatant was discarded and the cell pellet was resuspended in ⁇ 1 mL RBC lysis buffer (ebiosciences). Cells were centrifuged for 5 minutes at 1300 rpm at 4 °C. Supernatant was discarded and the cell pellet was resuspended in 500 pL (for spinal cord and lymph nodes) or 2 mL (for spleen) of RPMI + 2% FBS. Cells were counted on Vi-cell cell viability analyzer (Beckman Coulter). 150 pl of cell suspension was placed in 96 well U bottom plates for FACS staining.
  • FS fetal bovine serum
  • Plated cells were centrifuged for 4 minutes at 1300 rpm at 4 °C.
  • Human Fc block (1:200) and Live/Dead fixable dead stain (Thermo Fisher scientific) was added in 100 pL volume of PBS, and cells were incubated for 15 minutes at 4 °C.
  • BD cell staining buffer FBS; BD biosciences
  • 10 pL of MOG tetramer MOG 35-55, MBL international corporation
  • 50 pL of cell staining buffer containing surface antibodies was added and the cells were further incubated for 20 minutes at 4 °C.
  • Cells were centrifuged and washed twice in 150 pL volume of BD cell staining buffer.
  • For surface staining panel the cells were incubated in 100 pL of BD cytofix (BD biosciences) for 10 minutes at 4 °C.
  • Cells were centrifuged and washed twice in 150 pL volume of BD cell staining buffer.
  • Cells were resuspended in 250 pL of BD cell staining buffer for FACS analysis.
  • Intracellular Staining Following surface staining as described above the cells were centrifuged and washed twice in 150 pL volume of BD cell staining buffer. Following which intracellular staining was carried out using FoxP3/Transcription factor staining buffer set according to manufacturer’s protocol (Thermofisher). Cells were stained with intracellular antibodies for 30 minutes at 4 °C. Cells were centrifuged and washed twice in 150 pL volume of BD cell staining buffer. Cells were resuspended in 250 pL of BD cell staining buffer for FACS analysis.
  • FACS was performed on BD LSRII and analysis performed on FlowJo software (BD biosciences).
  • Antibodies other than those to RORgt and 3P10 were procured from Biolegend.
  • Antibody to RORgt (B2D) was procured from BD Biosciences.
  • 3P 10 is an inhibitory anti-GFRAL antibody that blocks GFRAL binding to
  • RET to antagonize GDF15 signaling without affecting GDF15 binding to GFRAL and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:22.
  • GDF15 Analog 1 is a complex comprising a first heterodimer and a second heterodimer, wherein each of the first heterodimer and the second heterodimer consists of a first polypeptide and a second polypeptide, wherein the first polypeptide consists of the amino acid sequence of SEQ ID NO: 13 and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 15, and wherein the first heterodimer dimerizes with the second heterodimer.
  • GDF15 Analog 2 is a homodimer comprising a first polypeptide and a second polypeptide, wherein each of the first polypeptide and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 7.
  • Donor mice female B6.PL-Thyla/CyJ and recipient mice (female C57BL/6), purchased from The Jackson Laboratory, ME, USA, were around 20 grams and approximately 9-week-old at the beginning of the study. The animals were kept under a 12-hour-light/dark cycle under controlled temperature (22 ⁇ 2°C) and humidity (50% ⁇ 20%) with access to food and water ad libitum. Donor mice were immunized with MOG/CFA (from Hooke lab) to induce experimental autoimmune encephalomyelitis (EAE) using a standard protocol. The signs of EAE were scored as described previously (Selvaraj et al., J. Biol. Chem.
  • MOG/CFA from Hooke lab
  • T cell medium DMEM media enriched with 10% FBS, 2 mM L-glutamine, 50 pM 2-mercaptoethanol, 1 mM nonessential amino acids, sodium pyruvate, and penicillin/streptomycin
  • T cell medium DMEM media enriched with 10% FBS, 2 mM L-glutamine, 50 pM 2-mercaptoethanol, 1 mM nonessential amino acids, sodium pyruvate, and penicillin/streptomycin
  • MOG Tocris Bioscience
  • recombinant murine IL-12 25 ng/ml
  • murine IL-23 25 ng/ml
  • anti-IL-4 I Opg/ml
  • mice were injected intraperitoneally into recipients.
  • PTX administration as described above for EAE induction and mice were weighed and assessed daily to record behavioral and neurological signs on the seventh day after cell transfer.
  • the donor mice were dosed with 1 mg/kg GDF15 Analog 1 or anti-KLH one day prior to MOG/CFA immunization in donor mice.
  • the recipient mice were dosed with 1 mg/kg GDF15 Analog 1 or anti-KLH at day 10, 17, and 24 post receiving donor immune cells.
  • T cell adoptive transfer-induced inflammatory bowel disease (IBD) model T cell adoptive transfer-induced inflammatory bowel disease (IBD) model
  • mice Female NOD, NOD/ShiLtJ mice (Stock No: 001976) around 19 grams approximately 6 weeks old (The Jackson Laboratory, ME, USA) were used. The animals were kept in the clean room under a 12-hour-light/dark cycle under controlled temperature (22 ⁇ 2°C) and humidity (50% ⁇ 20%) with access to food and water ad libitum.
  • mice spontaneously develop autoimmune diabetes at about 12-14 weeks of age. Starting from the age of 6 weeks, mice were subcutaneously injected with GDF15 Analog 1 or mouse anti-KLH proteins weekly for 18 weeks. Body weight and blood glucose were monitored weekly. Mice with blood glucose level at 250 mg/dL or above for two consecutive weeks were called diabetic and euthanized.
  • Cuprizone model 6-week-old male C57BL/6 mice from Jackson Lab were used for the studies.
  • the diet containing 0.2% cuprizone (CPZ) was purchased from Envigo (Envigo, TD.140803).
  • Mice were fed with CPZ-containing diet for 5 weeks, during which fresh food pellets were replaced every 3 to 5 days. The mice were euthanized on week 3 or week 5 and the whole brain were harvested for immunohistochemistry and pathology analyses.
  • the mice were fed with CPZ-containing diet for 5 weeks, followed by feeding with normal chow for 2 weeks to allow for remyelination. The mice were then euthanized on week 7 and the whole brain were harvested for immunohistochemistry and pathology analyses.
  • the whole colon was fixed as longitudinal segments in 10% neutral buffered formalin, processed to paraffin, and embedded creating strips to visualize the full height of the colonic glands.
  • the slides were stained for hematoxylin and eosin on the Leica Autostainer XL (Leica Biosystems, Buffalo Grove, IL).
  • the colon was evaluated for the thickness of the colonic mucosa from the surface epithelium to the deep lamina basement at the junction with the muscularis mucosa using the Visiopharm software (Visiopharm A/S, Horsholm, Denmark). This assessment was performed in representative areas of the proximal, mid and distal colon.
  • the LFB staining was performed by hand as per the manufacturer’s instructions.
  • the staining for IBA1 and GFAP was performed on the Leica Bond Rx autostainer (Leica Biosystems, Buffalo Grove, IL).
  • the slides were evaluated visually for differences between the control group and the CPZ model. IBA1 and GFAP expression was assessed by image analysis in hand-drawn specific areas of the brain using the Visiopharm software (Visiopharm A/S, Horsholm, Denmark).
  • the slides stained with LFB were graded twice blindly for demyelination which was graded from 0 (none) to 4 (complete demyelination).
  • Prophylactic dosing of EAE mice with anti-GFRAL antibody 3P10 blocked the effect of GDF15 Analog 1, indicating that it is a GFRAL-dependent mechanism (FIG. 1 and FIG. 2).
  • Prophylactic dosing of GDF15 Analog 1 did not show EAE blocking effect when dosed in GFRAL knockout mice, confirming the GFRAL-dependent mechanism (FIG. 3).
  • GDF15 Analog 1 prophylactically and therapeutically robustly improved the outcome of autoimmune encephalomyelitis in a well-validated animal model of multiple sclerosis.
  • GDF15 Analog 1 In a relapsing-remitting EAE model in which SJL mice were immunized with PLP139-151 peptide, prophylactic dosing of GDF15 Analog 1 blocked the onset of disease. In the same model, therapeutic dosing of GDF15 Analog 1 ameliorated disease progression and reduced EAE severity despite pathogenic immune cell infiltration into the CNS (FIG. 13).
  • Example 2 Effects of GDF 15 Polypeptide in Inflammatory Bowel Disease
  • IBD inflammatory bowel disease
  • GDF 15 Analog 1 significantly reduced the spleen weight and spleen weight/body weight ratio (FIG. 14), suggesting a systemic reduction of inflammation by GDF 15 Analog 1.
  • GDF 15 Analog 1 dosing at 1 mg/kg also reduced the colon weight and colon weight/body weight ratio without affecting colon length (FIG. 15).
  • GDF 15 Analog 1 also reduced the colon mucosal thickening, a hallmark of epithelium proliferation in response to inflammation (FIG. 16A and 16B). As expected, GDF 15 Analog 1 caused a dose-dependent weight loss at the onset of the study demonstrating that the metabolic effect of GDF 15 is preserved in this model (FIG. 17). All these data show that a GDF 15 polypeptide including a GDF 15 analog in the treatment and prevention of autoimmune diseases such as inflammatory bowel disease.
  • GDF 15 polypeptide The effect of a GDF 15 polypeptide on autoimmune disease was tested in a spontaneous diabetes model NOD mice.
  • Administration of GDF 15 Analog 1 lowered blood glucose levels, lowered body weight, and reduced the incidence of diabetes development in a dose-dependent manner (FIG. 18 and FIG. 19).
  • FIG. 18 and FIG. 19 These data show that a GDF 15 polypeptide including a GDF 15 analog in the treatment and prevention of autoimmune diseases such as type I diabetes.
  • Example 4 Effects of GDF15 Polypeptide in CNS Demyelination [00179] The effect of GDF15 polypeptides on CNS demyelination was studied. CNS demyelination happens in progressive MS, including primary progressive MS and secondary progressive MS.
  • mice was fed with 0.2% cuprizone (CPZ)-containing diet.
  • Cuprizone resulted in a loss of myeline sheath, which was detected by loss of Luxol fast blue (LFB) staining, in the corpus collosum (CC) of the brain.
  • LLB Luxol fast blue
  • CC corpus collosum
  • IBA1 staining a loss of myeline sheath
  • GDF15 Analog 1 Prophylactic treatment of mice with GDF15 Analog 1 protected the animals from losing myeline sheath and suppressed the microglia activation (FIG. 20A and 20B).
  • IBA1 microglia
  • FIG. 21 In addition to corpus collosum, activation of microglia (IBA1) in hippocampus observed in CPZ -treated mice was also suppressed by prophylactic treatment of GDF15 Analog 1 (FIG. 21).
  • mice were fed with 5 weeks of CPZ diet and then switched to normal chow for an additional 2 weeks. Some mice were treated with GDF15 Analog 1 throughout the study (Prophylactic treatment) or only after the withdrawal of CPZ-diet (Therapeutic treatment). Two weeks after CPZ withdrawal, the animals in all treatment groups recovered more LFB staining than in the control (anti-KLH) group. In fact, most of the animals in all treatment groups recovered LFB staining (LFB grade 0) in CC (FIG. 23). This indicates GDF15 Analog 1 plays a beneficial role in remyelination.

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Abstract

La présente divulgation concerne des méthodes de traitement et de prévention de troubles auto-immuns (par exemple, la sclérose en plaques (SEP)), lesdites méthodes comprenant l'administration à un sujet (par exemple, un être humain) en ayant besoin d'une quantité thérapeutiquement efficace d'un polypeptide de facteur 15 de différenciation et de croissance (GDF15). La présente divulgation concerne également une méthode de réduction ou de blocage de l'infiltration de cellules immunitaires pathogènes dans le système nerveux central d'un sujet, ladite méthode comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un polypeptide GDF15. La présente divulgation concerne également des polypeptides GDF15 associés, des procédés de fabrication de ceux-ci, et des compositions pharmaceutiques les comprenant.
PCT/US2023/062564 2022-02-14 2023-02-14 Polypeptides gdf15 pour le traitement et la prévention de maladies auto-immunes Ceased WO2023154953A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12173060B2 (en) 2014-10-31 2024-12-24 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders

Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110262393A1 (en) * 2008-11-14 2011-10-27 Medipost Co., Ltd. Composition comprising mesenchymal stem cells or culture solution of mesenchymal stem cells for the prevention or treatment of neural diseases
US8192735B2 (en) 2004-04-13 2012-06-05 St Vincent's Hospital Sydney Limited Method for modulating appetite
US8216805B2 (en) 1995-03-01 2012-07-10 Genentech, Inc. Knobs and holes heteromeric polypeptides
WO2012138919A2 (fr) 2011-04-08 2012-10-11 Amgen Inc. Méthode de traitement ou d'amélioration de troubles métaboliques à l'aide du facteur 15 de différenciation de croissance (gdf-15)
WO2013113008A1 (fr) 2012-01-26 2013-08-01 Amgen Inc. Polypeptides du facteur de croissance et de différenciation 15 (gdf-15)
WO2013148117A1 (fr) 2012-03-27 2013-10-03 Ngm Biopharmaceuticals, Inc. Compositions et méthodes d'utilisation pour le traitement de troubles métaboliques
US20140213511A1 (en) 2013-01-30 2014-07-31 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
WO2014120619A2 (fr) 2013-01-30 2014-08-07 Ngm Biopharmaceuticals, Inc. Compositions et procédés à utiliser pour le traitement de troubles métaboliques
WO2015017710A1 (fr) 2013-07-31 2015-02-05 Amgen Inc. Constructions contenant le facteur 15 de différentiation de croissance (gdf-15)
WO2015200078A1 (fr) 2014-06-23 2015-12-30 Novartis Ag Acides gras et leur utilisation dans la conjugaison de biomolécules
US20160031960A1 (en) 2014-07-30 2016-02-04 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
US20160120999A1 (en) 2014-10-31 2016-05-05 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
WO2017109706A1 (fr) 2015-12-22 2017-06-29 Novartis Ag Méthodes de traitement ou d'amélioration de troubles métaboliques à l'aide du facteur-15 de croissance et de différenciation (gdf-15)
WO2017172260A1 (fr) 2016-03-31 2017-10-05 Ngm Bioparmaceuticals, Inc. Protéines de liaison et leurs procédés d'utilisation
US20170327560A1 (en) 2016-05-10 2017-11-16 Janssen Biotech, Inc. Gdf15 fusion proteins and uses thereof
WO2018071493A1 (fr) 2016-10-12 2018-04-19 Janssen Biotech, Inc. Procédés de criblage de modulateurs d'une activité biologique de type gdf15
WO2018215525A1 (fr) 2017-05-23 2018-11-29 Novo Nordisk A/S Composés mic-1 et utilisations associées
US20190030903A1 (en) 2017-07-31 2019-01-31 Seiko Epson Corporation Ink refill container
WO2019195091A1 (fr) 2018-04-06 2019-10-10 Eli Lilly And Company Composés agonistes du facteur de différenciation de croissance 15 et leurs procédés d'utilisation
WO2020084496A1 (fr) 2018-10-22 2020-04-30 Janssen Pharmaceutica Nv Protéines de fusion peptide 1 (glp1) de type glucagon-facteur 15 de différenciation de croissance (gdf15) et utilisations associées
WO2020104948A1 (fr) 2018-11-20 2020-05-28 Janssen Pharmaceutica Nv Analogues de gdf15 et procédés destinés à être utilisés pour diminuer le poids corporel et/ou réduire l'ingestion d'aliments
WO2020185533A1 (fr) 2019-03-08 2020-09-17 Amgen Inc. Polythérapie par facteur de différenciation de croissance 15
WO2020218827A1 (fr) 2019-04-23 2020-10-29 주식회사 엘지화학 Polypeptide de fusion comprenant une région fc d'immunoglobuline et gdf15
US20210147500A1 (en) 2018-04-09 2021-05-20 Amgen Inc. Growth differentiation factor 15 fusion proteins

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8216805B2 (en) 1995-03-01 2012-07-10 Genentech, Inc. Knobs and holes heteromeric polypeptides
US8192735B2 (en) 2004-04-13 2012-06-05 St Vincent's Hospital Sydney Limited Method for modulating appetite
US20110262393A1 (en) * 2008-11-14 2011-10-27 Medipost Co., Ltd. Composition comprising mesenchymal stem cells or culture solution of mesenchymal stem cells for the prevention or treatment of neural diseases
WO2012138919A2 (fr) 2011-04-08 2012-10-11 Amgen Inc. Méthode de traitement ou d'amélioration de troubles métaboliques à l'aide du facteur 15 de différenciation de croissance (gdf-15)
WO2013113008A1 (fr) 2012-01-26 2013-08-01 Amgen Inc. Polypeptides du facteur de croissance et de différenciation 15 (gdf-15)
US20170291929A1 (en) 2012-01-26 2017-10-12 Amgen Inc. Growth Differentiation Factor 15 (GDF-15) Polypeptides
US20150023960A1 (en) 2012-03-27 2015-01-22 NGM Biopharmaceuticals, Inc Compositions and Methods of Use for Treating Metabolic Disorders
WO2013148117A1 (fr) 2012-03-27 2013-10-03 Ngm Biopharmaceuticals, Inc. Compositions et méthodes d'utilisation pour le traitement de troubles métaboliques
US20140213511A1 (en) 2013-01-30 2014-07-31 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
WO2014120619A2 (fr) 2013-01-30 2014-08-07 Ngm Biopharmaceuticals, Inc. Compositions et procédés à utiliser pour le traitement de troubles métaboliques
US20160200787A1 (en) 2013-01-30 2016-07-14 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
WO2015017710A1 (fr) 2013-07-31 2015-02-05 Amgen Inc. Constructions contenant le facteur 15 de différentiation de croissance (gdf-15)
WO2015200078A1 (fr) 2014-06-23 2015-12-30 Novartis Ag Acides gras et leur utilisation dans la conjugaison de biomolécules
US20160031960A1 (en) 2014-07-30 2016-02-04 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
WO2016018931A1 (fr) 2014-07-30 2016-02-04 Ngm Biopharmaceuticals, Inc. Compositions et méthodes d'utilisation pour le traitement de troubles métaboliques
WO2016069921A1 (fr) 2014-10-31 2016-05-06 Ngm Biopharmaceuticals, Inc. Compositions et leurs méthodes d'utilisation pour le traitement de troubles métaboliques
US20160120999A1 (en) 2014-10-31 2016-05-05 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders
WO2017109706A1 (fr) 2015-12-22 2017-06-29 Novartis Ag Méthodes de traitement ou d'amélioration de troubles métaboliques à l'aide du facteur-15 de croissance et de différenciation (gdf-15)
WO2017172260A1 (fr) 2016-03-31 2017-10-05 Ngm Bioparmaceuticals, Inc. Protéines de liaison et leurs procédés d'utilisation
US20170327560A1 (en) 2016-05-10 2017-11-16 Janssen Biotech, Inc. Gdf15 fusion proteins and uses thereof
WO2018071493A1 (fr) 2016-10-12 2018-04-19 Janssen Biotech, Inc. Procédés de criblage de modulateurs d'une activité biologique de type gdf15
WO2018215525A1 (fr) 2017-05-23 2018-11-29 Novo Nordisk A/S Composés mic-1 et utilisations associées
US20190030903A1 (en) 2017-07-31 2019-01-31 Seiko Epson Corporation Ink refill container
WO2019195091A1 (fr) 2018-04-06 2019-10-10 Eli Lilly And Company Composés agonistes du facteur de différenciation de croissance 15 et leurs procédés d'utilisation
US20190309033A1 (en) 2018-04-06 2019-10-10 Eli Lilly And Company Growth differentiation factor 15 agonist compounds and methods of using the same
US20210147500A1 (en) 2018-04-09 2021-05-20 Amgen Inc. Growth differentiation factor 15 fusion proteins
WO2020084496A1 (fr) 2018-10-22 2020-04-30 Janssen Pharmaceutica Nv Protéines de fusion peptide 1 (glp1) de type glucagon-facteur 15 de différenciation de croissance (gdf15) et utilisations associées
WO2020104948A1 (fr) 2018-11-20 2020-05-28 Janssen Pharmaceutica Nv Analogues de gdf15 et procédés destinés à être utilisés pour diminuer le poids corporel et/ou réduire l'ingestion d'aliments
WO2020185533A1 (fr) 2019-03-08 2020-09-17 Amgen Inc. Polythérapie par facteur de différenciation de croissance 15
WO2020218827A1 (fr) 2019-04-23 2020-10-29 주식회사 엘지화학 Polypeptide de fusion comprenant une région fc d'immunoglobuline et gdf15

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "2021 Medicines in Development: Health Equity Alzheimer's Disease Product Name Sponsor Indication Development Phase AAT-009 AskAt Alzheimer's disease Phase I completed (5-HT4 partial agonist)", 9 August 2021 (2021-08-09), pages 106 - 106, XP093035704, Retrieved from the Internet <URL:https://web.archive.org/web/20210809034834if_/https://phrma.org/-/media/Project/PhRMA/PhRMA-Org/PhRMA-Org/PDF/MID-Reports/2021-MID_Health-Equity_Drug-List.pdf> [retrieved on 20230329] *
ANONYMOUS: "Macrophage Inhibitory Cytokine 1: A new treatment for MS? - MS Australia", 8 December 2021 (2021-12-08), pages 1 - 4, XP093035106, Retrieved from the Internet <URL:https://web.archive.org/web/20211208210126/https://www.msaustralia.org.au/project/macrophage-inhibitory-cytokine-1-a-new-treatment-for-ms/> [retrieved on 20230327] *
ANONYMOUS: "Will Novo's big thinking in obesity pay off? | Evaluate", 15 April 2020 (2020-04-15), pages 1 - 6, XP093035706, Retrieved from the Internet <URL:https://www.evaluate.com/vantage/articles/events/company-events/will-novos-big-thinking-obesity-pay> [retrieved on 20230329] *
ARMOUR KL. ET AL., EUR J IMMUNOL., vol. 29, no. 8, 1999, pages 2613 - 24
ARTZ ANNETTE ET AL: "GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-[beta]RII heterodimer", BLOOD, vol. 128, no. 4, 28 July 2016 (2016-07-28), US, pages 529 - 541, XP093035275, ISSN: 0006-4971, Retrieved from the Internet <URL:https://watermark.silverchair.com/529.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA78wggO7BgkqhkiG9w0BBwagggOsMIIDqAIBADCCA6EGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMniLI9Se_GbkLaocnAgEQgIIDclI61rF3dA2JWtogVWnCeRZJOCcjjL4P8J4WCOJcOjk5AUNw8RbY5th-fLz3a-htUzTMvK-fBHhBZ8w8fjRtRRpH6PB9aTc4> DOI: 10.1182/blood-2016-01-696617 *
BENICHOU ET AL., CELL METABOLISM, vol. 35, 2023, pages 1 - 13
BOUTI PANAGIOTA ET AL: "[beta]2 Integrin Signaling Cascade in Neutrophils: More Than a Single Function", FRONTIERS IN IMMUNOLOGY, vol. 11, 18 February 2021 (2021-02-18), XP093035429, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930317/pdf/fimmu-11-619925.pdf> DOI: 10.3389/fimmu.2020.619925 *
EDELMAN, G.M. ET AL., PROC. NATL. ACAD. USA, vol. 63, 1969, pages 78 - 85
FAIRLIE ET AL., J. LEUKOC. BIOL, vol. 65, 1999, pages 2 - 5
GABRIELLE L. GOLDBERG ET AL: "G-CSF and Neutrophils Are Nonredundant Mediators of Murine Experimental Autoimmune Uveoretinitis", THE AMERICAN JOURNAL OF PATHOLOGY, vol. 186, no. 1, 1 January 2016 (2016-01-01), US, pages 172 - 184, XP055717568, ISSN: 0002-9440, DOI: 10.1016/j.ajpath.2015.09.008 *
HA ET AL., FRONT. IMMUNOL., vol. 7, pages 394
HIROSHI KATAYAMA: "Development of psoriasis by continuous neutrophil infiltration into the epidermis", EXPERIMENTAL DERMATOLOGY, BLACKWELL MUNSGAARD, COPENHAGEN; DK, vol. 27, no. 10, 14 August 2018 (2018-08-14), pages 1084 - 1091, XP071778688, ISSN: 0906-6705, DOI: 10.1111/EXD.13746 *
IDUSOGIE EE ET AL., J IMMUNOL., vol. 164, no. 8, 2000, pages 4178 - 84
JONATHAN J GRIST ET AL: "Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment", EUROPEAN JOURNAL OF IMMUNOLOGY, WILEY-VCH, HOBOKEN, USA, vol. 48, no. 7, 16 May 2018 (2018-05-16), pages 1199 - 1210, XP071227998, ISSN: 0014-2980, DOI: 10.1002/EJI.201747442 *
MOSCHOVAKI-FILIPPIDOU FOTEINI ET AL: "Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 19, 23 September 2020 (2020-09-23), pages 6978, XP093034774, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583818/pdf/ijms-21-06978.pdf> DOI: 10.3390/ijms21196978 *
MÜLLER TIMO D ET AL: "Anti-obesity drug discovery: advances and challenges", NATURE REVIEWS DRUG DISCOVERY, NATURE PUBLISHING GROUP, GB, vol. 21, no. 3, 23 November 2021 (2021-11-23), pages 201 - 223, XP037710234, ISSN: 1474-1776, [retrieved on 20211123], DOI: 10.1038/S41573-021-00337-8 *
NEEDLEMANWUNSCH, J. MOL. BIOL., vol. 48, 1970, pages 443
NICOLÁS FISSOLO ET AL: "Treatment with MOG-DNA vaccines induces CD4+CD25+FoxP3+ regulatory T cells and up-regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis", JOURNAL OF NEUROINFLAMMATION, BIOMED CENTRAL LTD., LONDON, GB, vol. 9, no. 1, 22 June 2012 (2012-06-22), pages 139, XP021133235, ISSN: 1742-2094, DOI: 10.1186/1742-2094-9-139 *
PEARSONLIPMAN, PROC. NAT'L. ACAD. SCI. USA, vol. 85, 1988, pages 2444
SELVARAJ ET AL., J. BIOL. CHEM., vol. 284, 2009, pages 26070 - 84
SHIELDS RL ET AL., J BIOL CHEM., vol. 276, no. 9, 2001, pages 6591 - 604
SMITHWATERMAN, ADV. APPL. MATH., vol. 2, 1981, pages 482
STEURER W. ET AL., J IMMUNOL., vol. 155, no. 3, 1995, pages 1165 - 74
TSAI VW ET AL., PLOS ONE, vol. 8, no. 2, 2013, pages e55174
VAN MUNSTERUITDEHAAG, CNS DRUGS, vol. 31, no. 3, 2017, pages 217 - 236
XIONG ET AL., SCI. TRANSL. MED., vol. 9, 2017, pages eaan8732

Cited By (1)

* Cited by examiner, † Cited by third party
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US12173060B2 (en) 2014-10-31 2024-12-24 Ngm Biopharmaceuticals, Inc. Compositions and methods of use for treating metabolic disorders

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